Daily Papers

Molecular discovery requires navigating vast combinatorial search spaces while balancing competing biological objectives. AI agents can automate expert-defined molecular design protocols, but automation alone does not address how to optimize workflows for new tasks or improve their development through experience. Here we introduce MoLRSI, an AI agent that combines systematic optimization of workflows and model architectures with persistent cross-task memory to recursively improve its search policy for molecular discovery. Workflow performance, refinement outcomes, and execution feedback guide subsequent searches, allowing the agent to improve both its workflows and its strategy for developing them. We evaluate MoLRSI in two challenging molecular discovery settings that require balancing competing properties. In antibiotic discovery, MoLRSI developed a screening workflow balancing antibacterial activity, cytotoxicity and structural novelty, achieving an experimental hit rate of 15.9%, compared with 8.7% for a previous expert-led workflow using the same training data and screening library. In de novo peptide-MHC binder design, MoLRSI developed workflows that jointly consider target binding and specificity, producing eight experimentally validated hits against MART-1 and SARS-CoV-1 pMHCs with preferential binding over tested off-targets while Claude Science completely failed. These findings demonstrate how experience-guided workflow optimization can address competing discovery objectives while improving the search strategies used in subsequent campaigns.

The success of language models, especially transformer-based architectures, has trickled into other domains giving rise to "scientific language models" that operate on small molecules, proteins or polymers. In chemistry, language models contribute to accelerating the molecule discovery cycle as evidenced by promising recent findings in early-stage drug discovery. Here, we review the role of language models in molecular discovery, underlining their strength in de novo drug design, property prediction and reaction chemistry. We highlight valuable open-source software assets thus lowering the entry barrier to the field of scientific language modeling. Last, we sketch a vision for future molecular design that combines a chatbot interface with access to computational chemistry tools. Our contribution serves as a valuable resource for researchers, chemists, and AI enthusiasts interested in understanding how language models can and will be used to accelerate chemical discovery.

Large language models (LLMs) are introducing a paradigm shift in molecular discovery by enabling text-guided interaction with chemical spaces through natural language, symbolic notations, with emerging extensions to incorporate multi-modal inputs. To advance the new field of LLM for molecular discovery, this survey provides an up-to-date and forward-looking review of the emerging use of LLMs for two central tasks: molecule generation and molecule optimization. Based on our proposed taxonomy for both problems, we analyze representative techniques in each category, highlighting how LLM capabilities are leveraged across different learning settings. In addition, we include the commonly used datasets and evaluation protocols. We conclude by discussing key challenges and future directions, positioning this survey as a resource for researchers working at the intersection of LLMs and molecular science. A continuously updated reading list is available at https://github.com/REAL-Lab-NU/Awesome-LLM-Centric-Molecular-Discovery.

Multi-agent systems have emerged as a powerful paradigm for automating scientific discovery. To differentiate agent behavior in the multi-agent system, current frameworks typically assign generic role-based personas such as ''reviewer'' or ''writer'' or rely on coarse grained keyword-based personas. While functional, this approach oversimplifies how human scientists operate, whose contributions are shaped by their unique research trajectories. In response, we propose INDIBATOR, a framework for molecular discovery that grounds agents in individualized scientist profiles constructed from two modalities: publication history for literature-derived knowledge and molecular history for structural priors. These agents engage in multi-turn debate through proposal, critique, and voting phases. Our evaluation demonstrates that these fine-grained individuality-grounded agents consistently outperform systems relying on coarse-grained personas, achieving competitive or state-of-the-art performance. These results validate that capturing the ``scientific DNA'' of individual agents is essential for high-quality discovery.

Machine learning can accelerate molecular discovery by designing molecules and planning experiments. However, many scientific challenges demand molecules with very rare properties, and in this sparse setting, existing algorithms offer little gain over random guessing. We propose a method to efficiently search large regions of molecular space using algorithmically controlled stochastic synthesis. Rather than design, make and test individual molecules, we design and make complex mixtures, test them as a pool, then deconvolute the molecule-activity map. We optimize synthesis to encode maximal information. Theoretically, this approach can reduce the number of experiments required to find the optimal molecule among d candidates from O(d) to O(log d) or O(1). In simulation, on estimated protein fitness landscapes, it finds active molecules with an order of magnitude fewer experiments than existing Bayesian optimization methods.

Data-driven molecular discovery leverages artificial intelligence/machine learning (AI/ML) and generative modeling to filter and design novel molecules. Discovering novel molecules requires accurate out-of-distribution (OOD) predictions, but ML models struggle to generalize OOD. Currently, no systematic benchmarks exist for molecular OOD prediction tasks. We present BOOM, benchmarks for out-of-distribution molecular property predictions: a chemically-informed benchmark for OOD performance on common molecular property prediction tasks. We evaluate over 150 model-task combinations to benchmark deep learning models on OOD performance. Overall, we find that no existing model achieves strong generalization across all tasks: even the top-performing model exhibited an average OOD error 3x higher than in-distribution. Current chemical foundation models do not show strong OOD extrapolation, while models with high inductive bias can perform well on OOD tasks with simple, specific properties. We perform extensive ablation experiments, highlighting how data generation, pre-training, hyperparameter optimization, model architecture, and molecular representation impact OOD performance. Developing models with strong OOD generalization is a new frontier challenge in chemical ML. This open-source benchmark is available at https://github.com/FLASK-LLNL/BOOM

As vast databases of chemical identities become increasingly available, the challenge shifts to how we effectively explore and leverage these resources to study molecular properties. This paper presents an active learning approach for molecular discovery using Deep Kernel Learning (DKL), demonstrated on the QM9 dataset. DKL links structural embeddings directly to properties, creating organized latent spaces that prioritize relevant property information. By iteratively recalculating embedding vectors in alignment with target properties, DKL uncovers concentrated maxima representing key molecular properties and reveals unexplored regions with potential for innovation. This approach underscores DKL's potential in advancing molecular research and discovery.

Large language models (LLMs) are increasingly used in molecular discovery and structure elucidation, where decisions depend on physical observations. Existing evaluations primarily focus on end-to-end molecular reconstruction, where correct predictions do not necessarily indicate reliance on the supplied properties. We introduce MolP2SBench, a benchmark for molecular property-to-structure (P2S) reasoning in LLMs. Each task presents a masked molecular scaffold with given properties and asks the model to select the missing structure from plausible candidates. We shuffle or replace properties to test reliance on correct property-structure pairing and responsiveness to counterfactual property changes. A channel-wise leaderboard uses Property-Grounded Recovery (PGR), giving equal weight to source and counterfactual recovery. Evaluating seven models, we find that LLMs can use physical properties for structure prediction, but performance varies substantially across property types. Higher accuracy with a property does not necessarily imply greater responsiveness to it: a model may benefit more from ^1H NMR than from ^{13}C NMR, yet be less likely to change its prediction when the ^1H data is replaced. LLM performance also need not reflect the relative difficulty of these properties for human chemists. Although UV-Vis spectra provide less direct structural information than NMR spectra, Astra achieves higher accuracy with UV-Vis data than with NMR peaks. MolP2SBench supports studying how LLMs extract and use physical-property information, revealing patterns that may differ from conventional chemical intuition and providing a foundation for more reliably property-grounded models for molecular and quantum-chemical inference. Code and dataset: https://github.com/DUAL-Xiao/MolP2SBench.

Molecular science represents an important frontier for LLM-based agents. Unlike general agents that mainly operate over natural language, code, or web environments, molecular LLM agents must perceive, reason about, and act upon chemical objects across symbolic strings, molecular graphs, 3D conformations, spectra, simulations, and wet-lab measurements. Their capabilities depend on chemically faithful molecular perception, an LLM-centered agent framework, domain-specific tool grounding, and computational or experimental feedback, in addition to planning and tool use. This work develops a conceptual framework for molecular LLM agents from two complementary perspectives. First, we introduce an architectural view of molecular-agent design, covering molecular representation and perception, the agent framework, domain-specific toolboxes, and learning and optimization. Second, we propose a scientific autonomy ladder inspired by staged autonomy in engineering systems, categorizing agents into four levels: L1 assistive or fixed workflows, L2 adaptive computational agents, L3 feedback-aware physical experiment agents, and L4 scientific-agenda agents. Together, these two perspectives establish a comprehensive framework for comparing existing molecular LLM agents, identifying missing capabilities and deployment risks, and guiding the design, evaluation, and deployment of future agents in molecular discovery workflows.

Bioassay activity prediction is often data-limited because drug-discovery datasets rely on time-consuming and expensive wet-lab experiments for data generation and evaluation. This challenge has inspired recent research into molecular foundation models (MFMs), which aim to encode general-purpose chemical knowledge into molecular representations that generalize well in data-constrained scenarios. This paper presents Monroe, a new MFM with several innovations over the existing state of the art: increased scale allowing pre-training on over 81 million molecules from the PM6 quantum chemistry dataset; improved graph representation of stereochemistry; improved training losses including conformer denoising and embedding decorrelation; improved multi-task learning; and the use of a prior-data-fitted model (TabPFN) for downstream in-context prediction. Our evaluations use a principled pairwise comparison framework that measures statistically significant performance differences. Across established Polaris benchmarks, Monroe matches or exceeds existing MFMs, while on activity cliff benchmarks, designed to assess utility for molecular discovery, it achieves significant improvements over prior methods. Finally, ablation and transfer experiments show that PFN-based downstream predictors also substantially improve two leading existing models, MiniMol and CheMeleon, yielding new state-of-the-art variants we call MiniMol_PFN and CheMeleon_PFN, suggesting that our downstream adaptation strategy generalizes beyond Monroe. Source code is at github.com/blazejba/monroe.

Despite deep learning's success in chemistry, its impact is hindered by a lack of interpretability and an inability to resolve activity cliffs, where minor structural nuances trigger drastic property shifts. Current representation learning, bound by the similarity principle, often fails to capture these structural-activity discontinuities. To address this, we introduce MolEvolve, an evolutionary framework that reformulates molecular discovery as an autonomous, look-ahead planning problem. Unlike traditional methods that depend on human-engineered features or rigid prior knowledge, MolEvolve leverages a Large Language Model (LLM) to actively explore and evolve a library of executable chemical symbolic operations. By utilizing the LLM to cold start and an Monte Carlo Tree Search (MCTS) engine for test-time planning with external tools (e.g. RDKit), the system self-discovers optimal trajectories autonomously. This process evolves transparent reasoning chains that translate complex structural transformations into actionable, human-readable chemical insights. Experimental results demonstrate that MolEvolve's autonomous search not only evolves transparent, human-readable chemical insights, but also outperforms baselines in both property prediction and molecule optimization tasks.

Language models are revolutionizing the biochemistry domain, assisting scientists in drug design and chemical synthesis with high efficiency. Yet current approaches struggle between small language models prone to hallucination and limited knowledge retention, and large cloud-based language models plagued by privacy risks and high inference costs. To bridge this gap, we introduce ChemCRAFT, a novel framework leveraging agentic reinforcement learning to decouple chemical reasoning from knowledge storage. Instead of forcing the model to memorize vast chemical data, our approach empowers the language model to interact with a sandbox for precise information retrieval. This externalization of knowledge allows a locally deployable small model to achieve superior performance with minimal inference costs. To enable small language models for agent-calling ability, we build an agentic trajectory construction pipeline and a comprehensive chemical-agent sandbox. Based on sandbox interactions, we constructed ChemToolDataset, the first large-scale chemical tool trajectory dataset. Simultaneously, we propose SMILES-GRPO to build a dense chemical reward function, promoting the model's ability to call chemical agents. Evaluations across diverse aspects of drug design show that ChemCRAFT outperforms current cloud-based LLMs in molecular structure analysis, molecular optimization, and synthesis pathway prediction, demonstrating that scientific reasoning is not solely an emergent ability of model scale, but a learnable policy of tool orchestration. This work establishes a cost-effective and privacy-preserving paradigm for AI-aided chemistry, opening new avenues for accelerating molecular discovery with locally deployable agents. Code available at https://github.com/HowardLi1984/ChemCraft.

Molecular discovery, when formulated as an optimization problem, presents significant computational challenges because optimization objectives can be non-differentiable. Evolutionary Algorithms (EAs), often used to optimize black-box objectives in molecular discovery, traverse chemical space by performing random mutations and crossovers, leading to a large number of expensive objective evaluations. In this work, we ameliorate this shortcoming by incorporating chemistry-aware Large Language Models (LLMs) into EAs. Namely, we redesign crossover and mutation operations in EAs using LLMs trained on large corpora of chemical information. We perform extensive empirical studies on both commercial and open-source models on multiple tasks involving property optimization, molecular rediscovery, and structure-based drug design, demonstrating that the joint usage of LLMs with EAs yields superior performance over all baseline models across single- and multi-objective settings. We demonstrate that our algorithm improves both the quality of the final solution and convergence speed, thereby reducing the number of required objective evaluations. Our code is available at http://github.com/zoom-wang112358/MOLLEO

Large language models (LLMs) are on the rise for accelerating scientific discovery, most recently in advanced tasks such as generating valid scientific hypotheses. Yet in many discovery settings, the goal is not to identify a single best hypothesis since validation can be noisy and expensive, and scientists benefit from a set of high-quality alternative hypotheses that hedge against downstream uncertainty for the best solutions. Nevertheless, commonly used evolutionary search recipes tend to prioritize optimization over exploration in hypothesis generation, and the resulting selection pressure during the search process leads to diversity collapse. Motivated by these limitations, we formulate hypothesis search as a sampling problem, where the objective is to efficiently produce diverse, high-quality hypotheses under a fixed validation budget. Building on this perspective, we propose \ours, an evolutionary framework inspired by the classical parallel tempering algorithm that searches hypotheses at multiple temperature levels and enables principled information exchange across temperatures to improve exploration without disrupting convergence. Across domains including molecular discovery, equation discovery, and algorithm discovery, our approach consistently improves both hypothesis quality and diversity under the same validation budget, and produces candidates that remain robust under more expensive downstream computational validations.

Language-molecule models have emerged as an exciting direction for molecular discovery and understanding. However, training these models is challenging due to the scarcity of molecule-language pair datasets. At this point, datasets have been released which are 1) small and scraped from existing databases, 2) large but noisy and constructed by performing entity linking on the scientific literature, and 3) built by converting property prediction datasets to natural language using templates. In this document, we detail the L+M-24 dataset, which has been created for the Language + Molecules Workshop shared task at ACL 2024. In particular, L+M-24 is designed to focus on three key benefits of natural language in molecule design: compositionality, functionality, and abstraction.

Generating novel molecules with out-of-distribution properties is a major challenge in molecular discovery. While supervised learning methods generate high-quality molecules similar to those in a dataset, they struggle to generalize to out-of-distribution properties. Reinforcement learning can explore new chemical spaces but often conducts 'reward-hacking' and generates non-synthesizable molecules. In this work, we address this problem by integrating a state-of-the-art supervised learning method, STGG+, in an active learning loop. Our approach iteratively generates, evaluates, and fine-tunes STGG+ to continuously expand its knowledge. We denote this approach STGG+AL. We apply STGG+AL to the design of organic pi-functional materials, specifically two challenging tasks: 1) generating highly absorptive molecules characterized by high oscillator strength and 2) designing absorptive molecules with reasonable oscillator strength in the near-infrared (NIR) range. The generated molecules are validated and rationalized in-silico with time-dependent density functional theory. Our results demonstrate that our method is highly effective in generating novel molecules with high oscillator strength, contrary to existing methods such as reinforcement learning (RL) methods. We open-source our active-learning code along with our Conjugated-xTB dataset containing 2.9 million pi-conjugated molecules and the function for approximating the oscillator strength and absorption wavelength (based on sTDA-xTB).

Neural networks surround us, in the form of large language models, speech transcription systems, molecular discovery algorithms, robotics, and much more. Stripped of anything else, neural networks are compositions of differentiable primitives, and studying them means learning how to program and how to interact with these models, a particular example of what is called differentiable programming. This primer is an introduction to this fascinating field imagined for someone, like Alice, who has just ventured into this strange differentiable wonderland. I overview the basics of optimizing a function via automatic differentiation, and a selection of the most common designs for handling sequences, graphs, texts, and audios. The focus is on a intuitive, self-contained introduction to the most important design techniques, including convolutional, attentional, and recurrent blocks, hoping to bridge the gap between theory and code (PyTorch and JAX) and leaving the reader capable of understanding some of the most advanced models out there, such as large language models (LLMs) and multimodal architectures.

Large language models (LLMs) have shown remarkable potential in various domains, but they often lack the ability to access and reason over domain-specific knowledge and tools. In this paper, we introduced CACTUS (Chemistry Agent Connecting Tool-Usage to Science), an LLM-based agent that integrates cheminformatics tools to enable advanced reasoning and problem-solving in chemistry and molecular discovery. We evaluate the performance of CACTUS using a diverse set of open-source LLMs, including Gemma-7b, Falcon-7b, MPT-7b, Llama2-7b, and Mistral-7b, on a benchmark of thousands of chemistry questions. Our results demonstrate that CACTUS significantly outperforms baseline LLMs, with the Gemma-7b and Mistral-7b models achieving the highest accuracy regardless of the prompting strategy used. Moreover, we explore the impact of domain-specific prompting and hardware configurations on model performance, highlighting the importance of prompt engineering and the potential for deploying smaller models on consumer-grade hardware without significant loss in accuracy. By combining the cognitive capabilities of open-source LLMs with domain-specific tools, CACTUS can assist researchers in tasks such as molecular property prediction, similarity searching, and drug-likeness assessment. Furthermore, CACTUS represents a significant milestone in the field of cheminformatics, offering an adaptable tool for researchers engaged in chemistry and molecular discovery. By integrating the strengths of open-source LLMs with domain-specific tools, CACTUS has the potential to accelerate scientific advancement and unlock new frontiers in the exploration of novel, effective, and safe therapeutic candidates, catalysts, and materials. Moreover, CACTUS's ability to integrate with automated experimentation platforms and make data-driven decisions in real time opens up new possibilities for autonomous discovery.

Molecular optimization, which transforms a given input molecule X into another Y with desirable properties, is essential in molecular drug discovery. The traditional translating approaches, generating the molecular graphs from scratch by adding some substructures piece by piece, prone to error because of the large set of candidate substructures in a large number of steps to the final target. In this study, we present a novel molecular optimization paradigm, Graph Polish, which changes molecular optimization from the traditional "two-language translating" task into a "single-language polishing" task. The key to this optimization paradigm is to find an optimization center subject to the conditions that the preserved areas around it ought to be maximized and thereafter the removed and added regions should be minimized. We then propose an effective and efficient learning framework T&S polish to capture the long-term dependencies in the optimization steps. The T component automatically identifies and annotates the optimization centers and the preservation, removal and addition of some parts of the molecule, and the S component learns these behaviors and applies these actions to a new molecule. Furthermore, the proposed paradigm can offer an intuitive interpretation for each molecular optimization result. Experiments with multiple optimization tasks are conducted on four benchmark datasets. The proposed T&S polish approach achieves significant advantage over the five state-of-the-art baseline methods on all the tasks. In addition, extensive studies are conducted to validate the effectiveness, explainability and time saving of the novel optimization paradigm.

Molecular glue degraders have emerged as a promising strategy for targeted protein degradation by inducing ternary complex formation between an E3 ubiquitin ligase and a target protein. Despite their therapeutic potential, computational design of molecular glues remains largely unexplored. Unlike conventional structure-based drug design, molecular glue design is governed by the unknown protein-protein interface and requires the simultaneous modeling of ligand generation, protein-protein docking, and ternary complex assembly. In this work, we formulate molecular glue design as a ternary complex generation problem and propose a biology-inspired generative framework, TriGlue. Motivated by the mechanism of molecular glue action, we decompose ternary complex generation into two coupled stages: interface estimation and interface-conditioned complex generation. First, we develop an SE(3)-equivariant interface estimation module that predicts a geometrically constrained protein-protein interface from unbound monomer structures. Second, we introduce an interface-conditioned ternary flow matching network that jointly generates the molecular glue and predicts the rigid-body transformation required to assemble the ternary complex. Extensive experiments demonstrate that TriGlue generates chemically valid molecules and produces plausible ternary complexes, which highlight the potential of biology-inspired generative modeling for accelerating molecular glue discovery. Our code is available at https://github.com/yuliangyan0807/molecular-glue-design.

The rapid evolution of artificial intelligence in drug discovery encounters challenges with generalization and extensive training, yet Large Language Models (LLMs) offer promise in reshaping interactions with complex molecular data. Our novel contribution, InstructMol, a multi-modal LLM, effectively aligns molecular structures with natural language via an instruction-tuning approach, utilizing a two-stage training strategy that adeptly combines limited domain-specific data with molecular and textual information. InstructMol showcases substantial performance improvements in drug discovery-related molecular tasks, surpassing leading LLMs and significantly reducing the gap with specialized models, thereby establishing a robust foundation for a versatile and dependable drug discovery assistant.

Graph Neural Networks (GNNs) have been widely adopted for drug discovery with molecular graphs. Nevertheless, current GNNs are mainly good at leveraging short-range interactions (SRI) but struggle to capture long-range interactions (LRI), both of which are crucial for determining molecular properties. To tackle this issue, we propose a method that implicitly projects all original atoms into a few Neural Atoms, which abstracts the collective information of atomic groups within a molecule. Specifically, we explicitly exchange the information among neural atoms and project them back to the atoms' representations as an enhancement. With this mechanism, neural atoms establish the communication channels among distant nodes, effectively reducing the interaction scope of arbitrary node pairs into a single hop. To provide an inspection of our method from a physical perspective, we reveal its connection with the traditional LRI calculation method, Ewald Summation. We conduct extensive experiments on three long-range graph benchmarks, covering both graph-level and link-level tasks on molecular graphs. We empirically justify that our method can be equipped with an arbitrary GNN and help to capture LRI.

Generative models have the potential to accelerate key steps in the discovery of novel molecular therapeutics and materials. Diffusion models have recently emerged as a powerful approach, excelling at unconditional sample generation and, with data-driven guidance, conditional generation within their training domain. Reliably sampling from high-value regions beyond the training data, however, remains an open challenge -- with current methods predominantly focusing on modifying the diffusion process itself. In this paper, we develop context-guided diffusion (CGD), a simple plug-and-play method that leverages unlabeled data and smoothness constraints to improve the out-of-distribution generalization of guided diffusion models. We demonstrate that this approach leads to substantial performance gains across various settings, including continuous, discrete, and graph-structured diffusion processes with applications across drug discovery, materials science, and protein design.

Large Language Models have recently gained significant attention in scientific discovery for their extensive knowledge and advanced reasoning capabilities. However, they encounter challenges in effectively simulating observational feedback and grounding it with language to propel advancements in physical scientific discovery. Conversely, human scientists undertake scientific discovery by formulating hypotheses, conducting experiments, and revising theories through observational analysis. Inspired by this, we propose to enhance the knowledge-driven, abstract reasoning abilities of LLMs with the computational strength of simulations. We introduce Scientific Generative Agent (SGA), a bilevel optimization framework: LLMs act as knowledgeable and versatile thinkers, proposing scientific hypotheses and reason about discrete components, such as physics equations or molecule structures; meanwhile, simulations function as experimental platforms, providing observational feedback and optimizing via differentiability for continuous parts, such as physical parameters. We conduct extensive experiments to demonstrate our framework's efficacy in constitutive law discovery and molecular design, unveiling novel solutions that differ from conventional human expectations yet remain coherent upon analysis.

Scientific discovery requires identifying the scientific principles underlying observed phenomena to guide further investigation. As these empirical principles are often unknown in complex discovery processes, they are constructed via a hypotheses-to-principle pipeline to obtain recurring causalities from progressively accumulated observations during test-time discovery. However, constructing this knowledge requires substantial domain expertise, time, and effort, making this translation stage a bottleneck for scientific discovery. To address this limitation, we propose Principia, an LLM-based framework that constructs and continually refines scientific principles at test time. Drawing on how human researchers develop principles, Principia forms comparative causal hypotheses from related inputs and their observed outcomes, then synthesizes recurring relationships across these hypotheses into inductive principles. By applying the constructed hypotheses and inductive principles to the task, it obtains new observations, revises the hypotheses used based on these new observations, and reconstructs principles from the updated hypotheses, allowing scientific knowledge to continuously evolve throughout test-time discovery. Across benchmarks spanning molecular optimization, protein engineering, gene perturbation, and molecular property prediction, Principia outperforms baselines relying on internal knowledge, external sources, or experience summaries, while generating principles that are plausible and consistent with the scientific literature, demonstrating its effectiveness in constructing and refining task-specific hypotheses and principles at test time for scientific discovery. Our code is available at https://github.com/DongkiKim95/Principia.

Protein-ligand modeling underpins computational drug discovery and molecular design. Existing protein-ligand benchmarks typically evaluate whether a protein and ligand interact and how strongly they bind, through tasks such as binary binding prediction and affinity regression. However, these evaluations provide limited evidence of whether models can localize binding sites or identify the non-covalent interactions underlying molecular recognition. To address this gap, we introduce InteractBind, a large-scale protein-ligand dataset comprising approximately 100k protein-ligand pairs, together with a benchmark for fine-grained evaluation. The core fine-grained task is that of binding-site localization, which uses protein-residue and ligand-atom interaction maps spanning six major types of non-covalent interactions to assess whether model-derived interaction maps localize binding sites. InteractBind further includes binding affinity and protein similarity-controlled splits to support realistic generalization assessment. Using InteractBind, we evaluate eight existing sequence-based and interaction-aware models, assessing binary binding prediction and binding-site localization. Results reveal limited binding-site localization despite strong binary binding prediction, with marked variation across non-covalent interaction types. Overall, InteractBind establishes a benchmark paradigm that encourages the development of more interpretable and physically grounded protein-ligand models.

Large-scale cell microscopy screens are used in drug discovery and molecular biology research to study the effects of millions of chemical and genetic perturbations on cells. To use these images in downstream analysis, we need models that can map each image into a feature space that represents diverse biological phenotypes consistently, in the sense that perturbations with similar biological effects have similar representations. In this work, we present the largest foundation model for cell microscopy data to date, a new 1.9 billion-parameter ViT-G/8 MAE trained on over 8 billion microscopy image crops. Compared to a previous published ViT-L/8 MAE, our new model achieves a 60% improvement in linear separability of genetic perturbations and obtains the best overall performance on whole-genome biological relationship recall and replicate consistency benchmarks. Beyond scaling, we developed two key methods that improve performance: (1) training on a curated and diverse dataset; and, (2) using biologically motivated linear probing tasks to search across each transformer block for the best candidate representation of whole-genome screens. We find that many self-supervised vision transformers, pretrained on either natural or microscopy images, yield significantly more biologically meaningful representations of microscopy images in their intermediate blocks than in their typically used final blocks. More broadly, our approach and results provide insights toward a general strategy for successfully building foundation models for large-scale biological data.

Graph neural networks have moved from a niche representation-learning technique to the default model class wherever data carry relational structure. The interesting question is no longer whether message passing helps on a given dataset, but where graph structure earns its computational cost and where it does not. This survey organises the field around a single design space, derives the spectral and spatial formulations from shared first principles, and connects expressive power to the Weisfeiler-Leman hierarchy with explicit statements of what current architectures can and cannot separate. Against that methodological backbone we examine twelve application domains, among them recommendation and social networks, knowledge graphs and language-model integration, drug discovery and molecular property learning, healthcare and neuroscience, computer vision, traffic and urban computing, power and renewable-energy systems, wireless and sixth-generation networks, fraud and cybersecurity, industrial prognostics, materials science, and climate modelling. For each domain we specify the graph-construction choices and their costs, identify which architecture families dominate and why, and separate reported gains from artefacts of weak baselines or favourable splits. A cross-domain comparison exposes recurring patterns: heterophily and scale undercut the same models almost everywhere, temporal graphs remain harder than their static counterparts, and the architectures that top public leaderboards are seldom the ones that reach deployment. We treat over-smoothing, over-squashing, robustness, distribution shift, fairness, and explainability not as a closing checklist but as the constraints that decide adoption.

Generative molecular design is shaped by simple proxy benchmarks for drug-like properties and models pretrained on large pharmaceutical datasets. This combination yields strong benchmark metrics but limits transferability to domains structurally distinct from drug discovery. To overcome this limitation and drive discovery toward real, scientifically grounded targets, we introduce the Nanotechnology Molecular Optimization (NMO) Benchmark, which bridges machine learning (ML) and quantum materials science. NMO acts simultaneously as a rigorous testbed for the ML community and a discovery engine for nanotechnology research. The suite replaces proxy oracles with quantum simulations and introduces strict protocols that prioritize scientific utility over leaderboard-oriented overfitting. The physics-based NMO tasks impose hard structural constraints and rugged fitness landscapes, posing fundamentally new requirements on generative models. Notably, advanced molecular optimization methods underperform much simpler approaches on the NMO tasks. We develop a new baseline method identifying the critical components to solve the NMO tasks, including a novel representation for modeling structural constraints and a domain-agnostic pretraining strategy to eliminate pharmaceutical dataset bias. Our results surpass state-of-the-art physical properties and reveal previously unknown structural motifs, offering new insights for the nanotechnology community and demonstrating that ML can drive genuine scientific discovery.

In drug-discovery-related tasks such as virtual screening, machine learning is emerging as a promising way to predict molecular properties. Conventionally, molecular fingerprints (numerical representations of molecules) are calculated through rule-based algorithms that map molecules to a sparse discrete space. However, these algorithms perform poorly for shallow prediction models or small datasets. To address this issue, we present SMILES Transformer. Inspired by Transformer and pre-trained language models from natural language processing, SMILES Transformer learns molecular fingerprints through unsupervised pre-training of the sequence-to-sequence language model using a huge corpus of SMILES, a text representation system for molecules. We performed benchmarks on 10 datasets against existing fingerprints and graph-based methods and demonstrated the superiority of the proposed algorithms in small-data settings where pre-training facilitated good generalization. Moreover, we define a novel metric to concurrently measure model accuracy and data efficiency.

In molecular research, simulation \& design of molecules are key areas with significant implications for drug development, material science, and other fields. Current classical computational power falls inadequate to simulate any more than small molecules, let alone protein chains on hundreds of peptide. Therefore these experiment are done physically in wet-lab, but it takes a lot of time \& not possible to examine every molecule due to the size of the search area, tens of billions of dollars are spent every year in these research experiments. Molecule simulation \& design has lately advanced significantly by machine learning models, A fresh perspective on the issue of chemical synthesis is provided by deep generative models for graph-structured data. By optimising differentiable models that produce molecular graphs directly, it is feasible to avoid costly search techniques in the discrete and huge space of chemical structures. But these models also suffer from computational limitations when dimensions become huge and consume huge amount of resources. Quantum Generative machine learning in recent years have shown some empirical results promising significant advantages over classical counterparts.

Drug discovery typically consists of multiple steps, including identifying a target protein key to a disease's etiology, validating that interacting with this target could prevent symptoms or cure the disease, discovering a small molecule or biologic therapeutic to interact with it, and optimizing the candidate molecule through a complex landscape of required properties. Drug discovery related tasks often involve prediction and generation while considering multiple entities that potentially interact, which poses a challenge for typical AI models. For this purpose we present MAMMAL - Molecular Aligned Multi-Modal Architecture and Language - a method that we applied to create a versatile multi-task foundation model ibm/biomed.omics.bl.sm.ma-ted-458m that learns from large-scale biological datasets (2 billion samples) across diverse modalities, including proteins, small molecules, and genes. We introduce a prompt syntax that supports a wide range of classification, regression, and generation tasks. It allows combining different modalities and entity types as inputs and/or outputs. Our model handles combinations of tokens and scalars and enables the generation of small molecules and proteins, property prediction, and transcriptomic lab test predictions. We evaluated the model on 11 diverse downstream tasks spanning different steps within a typical drug discovery pipeline, where it reaches new SOTA in 9 tasks and is comparable to SOTA in 2 tasks. This performance is achieved while using a unified architecture serving all tasks, in contrast to the original SOTA performance achieved using tailored architectures. The model code and pretrained weights are publicly available at https://github.com/BiomedSciAI/biomed-multi-alignment and https://huggingface.co/ibm/biomed.omics.bl.sm.ma-ted-458m.

Automated drug discovery offers significant potential for accelerating the development of novel therapeutics by substituting labor-intensive human workflows with machine-driven processes. However, molecules generated by artificial intelligence may unintentionally infringe on existing patents, posing legal and financial risks that impede the full automation of drug discovery pipelines. This paper introduces PatentFinder, a novel multi-agent and tool-enhanced intelligence system that can accurately and comprehensively evaluate small molecules for patent infringement. PatentFinder features five specialized agents that collaboratively analyze patent claims and molecular structures with heuristic and model-based tools, generating interpretable infringement reports. To support systematic evaluation, we curate MolPatent-240, a benchmark dataset tailored for patent infringement assessment algorithms. On this benchmark, PatentFinder outperforms baseline methods that rely solely on large language models or specialized chemical tools, achieving a 13.8% improvement in F1-score and a 12% increase in accuracy. Additionally, PatentFinder autonomously generates detailed and interpretable patent infringement reports, showcasing enhanced accuracy and improved interpretability. The high accuracy and interpretability of PatentFinder make it a valuable and reliable tool for automating patent infringement assessments, offering a practical solution for integrating patent protection analysis into the drug discovery pipeline.

High-velocity clouds (HVCs) are composed of neutral hydrogen (HI) moving at velocities that deviate from the general rotational motion of the Milky Way. Currently, the origins of the HVCs remain poorly known due to the difficulty in determining their distance and the lack of any other suitable identification. Here we report the detection of a compact gas clump in HVC AC-I, which displays characteristics typical of a disk galaxy, named AC G185.0-11.5, using the HI observations. We estimated the distance of AC G185.0-11.5 to be about 277.7 kpc using the Baryonic Tully-Fisher relation and constrained its HI gas mass to be between 3.0*10^7 and 4.7*10^8 solar masses. The distance determination indicates that the HVC AC-I hosting AC G185.0-11.5 is an extragalactic object in the Local Group. The absence of molecular gas and an optical counterpart for AC G185.0-11.5 implies that it may be a rare dark galaxy.

Molecular property prediction is crucial for drug discovery and materials science, yet existing approaches suffer from limited interpretability, poor cross-task generalization, and lack of chemical reasoning capabilities. Traditional machine learning models struggle with task transferability, while specialized molecular language models provide little insight into their decision-making processes. To address these limitations, we propose MPPReasoner, a multimodal large language model that incorporates chemical reasoning for molecular property prediction. Our approach, built upon Qwen2.5-VL-7B-Instruct, integrates molecular images with SMILES strings to enable comprehensive molecular understanding. We develop a two-stage training strategy: supervised fine-tuning (SFT) using 16,000 high-quality reasoning trajectories generated through expert knowledge and multiple teacher models, followed by Reinforcement Learning from Principle-Guided Rewards (RLPGR). RLPGR employs verifiable, rule-based rewards that systematically evaluate chemical principle application, molecular structure analysis, and logical consistency through computational verification. Extensive experiments across 8 datasets demonstrate significant performance improvements, with MPPReasoner outperforming the best baselines by 7.91\% and 4.53\% on in-distribution and out-of-distribution tasks respectively. MPPReasoner exhibits exceptional cross-task generalization and generates chemically sound reasoning paths that provide valuable insights into molecular property analysis, substantially enhancing both interpretability and practical utility for chemists. Code is available at https://anonymous.4open.science/r/MPPReasoner-12687.

The discovery of next-generation photoinitiators for two-photon polymerization (TPP) is hindered by the absence of large, open datasets containing the quantum-chemical and photophysical properties required to model photodissociation and excited-state behavior. Existing molecular datasets typically provide only basic physicochemical descriptors and therefore cannot support data-driven screening or AI-assisted design of photoinitiators. To address this gap, we introduce QuantumChem-200K, a large-scale dataset of over 200,000 organic molecules annotated with eleven quantum-chemical properties, including two-photon absorption (TPA) cross sections, TPA spectral ranges, singlet-triplet intersystem crossing (ISC) energies, toxicity and synthetic accessibility scores, hydrophilicity, solubility, boiling point, molecular weight, and aromaticity. These values are computed using a hybrid workflow that integrates density function theory (DFT), semi-empirical excited-state methods, atomistic quantum solvers, and neural-network predictors. Using QuantumChem-200K, we fine tune the open-source Qwen2.5-32B large language model to create a chemistry AI assistant capable of forward property prediction from SMILES. Benchmarking on 3000 unseen molecules from VQM24 and ZINC20 demonstrates that domain-specific fine-tuning significantly improves accuracy over GPT-4o, Llama-3.1-70B, and the base Qwen2.5-32B model, particularly for TPA and ISC predictions central to photoinitiator design. QuantumChem-200K and the corresponding AI assistant together provide the first scalable platform for high-throughput, LLM-driven photoinitiator screening and accelerated discovery of photosensitive materials.

Molecular generation is a central challenge in drug discovery, requiring models that explore vast chemical space while satisfying diverse design constraints. We present Molexar, a unified multimodal molecular foundation model built on Fragment-SELFIES, a robust, fragment-aware molecular language with validity-preserving decoding and explicit fragment structure. A pretrained autoregressive decoder learns the Fragment-SELFIES syntax and molecular distribution; supervised fine-tuning (SFT) then trains the same decoder on condition-molecule pairs spanning scalar molecular properties, pharmacophore fingerprints, protein sequences, and binding pockets, injecting each condition by in-place replacement of value-token embeddings so that all generation modes share one autoregressive path. Molexar achieves strong efficiency at a small parameter count while matching or exceeding larger models. The pretrained model reaches 100% validity and high drug-likeness in unconditional and fragment-constrained generation; the SFT model follows single- and multi-property instructions and remains competitive on target-conditioned generation on the CrossDocked2020 test set. On MolGenBench, Molexar further generates molecules with favorable safety and potency. These results establish Molexar as a practical unified foundation for computational chemistry and drug-design workflows.

Assessing whether a molecule can be synthesised is a primary task in drug discovery. It enables computational chemists to filter for viable compounds or bias molecular generative models. The notion of synthesisability is dynamic as it evolves depending on the availability of key compounds. A common approach in drug discovery involves exploring the chemical space surrounding synthetically-accessible intermediates. This strategy improves the synthesisability of the derived molecules due to the availability of key intermediates. Existing synthesisability scoring methods such as SAScore, SCScore and RAScore, cannot condition on intermediates dynamically. Our approach, Leap, is a GPT-2 model trained on the depth, or longest linear path, of predicted synthesis routes that allows information on the availability of key intermediates to be included at inference time. We show that Leap surpasses all other scoring methods by at least 5% on AUC score when identifying synthesisable molecules, and can successfully adapt predicted scores when presented with a relevant intermediate compound.

Generative molecular design for drug discovery has very recently achieved a wave of experimental validation, with language-based backbones being the most common architectures employed. The most important factor for downstream success is whether an in silico oracle is well correlated with the desired end-point. To this end, current methods use cheaper proxy oracles with higher throughput before evaluating the most promising subset with high-fidelity oracles. The ability to directly optimize high-fidelity oracles would greatly enhance generative design and be expected to improve hit rates. However, current models are not efficient enough to consider such a prospect, exemplifying the sample efficiency problem. In this work, we introduce Saturn, which leverages the Augmented Memory algorithm and demonstrates the first application of the Mamba architecture for generative molecular design. We elucidate how experience replay with data augmentation improves sample efficiency and how Mamba synergistically exploits this mechanism. Saturn outperforms 22 models on multi-parameter optimization tasks relevant to drug discovery and may possess sufficient sample efficiency to consider the prospect of directly optimizing high-fidelity oracles.

Learning causal graphs from interventional data is a challenging problem with broad applications. In molecular biology, for example, a central goal is to uncover gene regulatory networks from large-scale perturbation data. An ideal algorithm for this task should scale to thousands of nodes, incorporate interventions even when their targets are unknown, quantify uncertainty, and provide identifiability guarantees. However, existing approaches---e.g. approaches using score-based optimization or approximate Bayesian inference---often fail to meet all of these criteria. To address these limitations, we develop Amortized Bayesian Causal Discovery of Extended Factor Graphs (ABCDEFG). Our method guarantees exact acyclicity, scales to graphs with thousands of nodes, and naturally handles interventions even when their targets are unknown. Additionally, ABCDEFG estimates a posterior distribution whose maximum a posteriori estimate provably identifies the true causal graph up to an equivalence class. On simulated datasets, ABCDEFG achieves state-of-the-art accuracy, producing a well-calibrated posterior distribution while outperforming previous score-based and approximate Bayesian methods. Applied to large-scale single-cell perturbation data, ABCDEFG identifies both established and novel gene targets of growth factors.

The discovery of novel materials and functional molecules can help to solve some of society's most urgent challenges, ranging from efficient energy harvesting and storage to uncovering novel pharmaceutical drug candidates. Traditionally matter engineering -- generally denoted as inverse design -- was based massively on human intuition and high-throughput virtual screening. The last few years have seen the emergence of significant interest in computer-inspired designs based on evolutionary or deep learning methods. The major challenge here is that the standard strings molecular representation SMILES shows substantial weaknesses in that task because large fractions of strings do not correspond to valid molecules. Here, we solve this problem at a fundamental level and introduce SELFIES (SELF-referencIng Embedded Strings), a string-based representation of molecules which is 100\% robust. Every SELFIES string corresponds to a valid molecule, and SELFIES can represent every molecule. SELFIES can be directly applied in arbitrary machine learning models without the adaptation of the models; each of the generated molecule candidates is valid. In our experiments, the model's internal memory stores two orders of magnitude more diverse molecules than a similar test with SMILES. Furthermore, as all molecules are valid, it allows for explanation and interpretation of the internal working of the generative models.

Drug discovery can be viewed as a combinatorial search over an immense chemical space, motivating the development of deep generative models for de novo molecular design. Among these, GPT-based molecular language models (MLM) have shown strong molecular design performance by learning chemical syntax and semantics from large-scale data. However, existing MLMs face two fundamental limitations: they inadequately capture the graph-structured nature of molecules when formulated as next-token prediction problems, and they typically lack explicit mechanisms for target-aware generation. Here, we propose SoftMol, a unified framework that co-designs molecular representation, model architecture, and search strategy for target-aware molecular generation. SoftMol introduces soft fragments, a rule-free block representation of SMILES that enables diffusion-native modeling, and develops SoftBD, the first block-diffusion molecular language model that combines local bidirectional diffusion with autoregressive generation under molecular structural constraints. To favor generated molecules with high drug-likeness and synthetic accessibility, SoftBD is trained on a carefully curated dataset named ZINC-Curated. SoftMol further integrates a gated Monte Carlo tree search to assemble fragments in a target-aware manner. Experimental results show that, compared with current state-of-the-art models, SoftMol achieves 100% chemical validity, improves binding affinity by 9.7%, yields a 2-3x increase in molecular diversity, and delivers a 6.6x speedup in inference efficiency. Code is available at https://github.com/szu-aicourse/softmol

Molecular understanding is central to advancing areas such as scientific discovery, yet Large Language Models (LLMs) struggle to understand molecular graphs effectively. Existing graph-LLM bridges often adapt the Q-Former-style connector with fixed-length static tokens, which is originally designed for vision tasks. These designs overlook stereochemistry and substructural context and typically require costly LLM-backbone fine-tuning, limiting efficiency and generalization. We introduce EDT-Former, an Entropy-guided Dynamic Token Transformer that generates tokens aligned with informative molecular patches, thereby preserving both local and global structural features for molecular graph understanding. Beyond prior approaches, EDT-Former enables alignment between frozen graph encoders and LLMs without tuning the LLM backbone (excluding the embedding layer), resulting in computationally efficient finetuning, and achieves stateof-the-art results on MoleculeQA, Molecule-oriented Mol-Instructions, and property prediction benchmarks (TDC, MoleculeNet), underscoring its effectiveness for scalable and generalizable multimodal molecular understanding

Current computational approaches for drug design typically focus on generating molecules conditioned on specific targets or general molecular properties, often neglecting the influence of disease context on target behavior and therapeutic outcomes. To address this gap, we introduce DrugGen-2, a novel generative model that designs small molecules conditioned on both disease ontology and target protein sequences. DrugGen-2 was developed by fine-tuning a pre-trained GPT-2 model on a curated dataset of approved drugs linked to their diseases and targets, using a two-step strategy of supervised fine-tuning followed by reinforcement learning via group relative policy optimization (GRPO). This process was guided by reward functions optimizing for chemical validity, novelty, diversity, and high predicted binding affinity. When evaluated on five protein targets relevant to diabetic nephropathy, DrugGen-2 significantly outperformed baseline models (DrugGPT and DrugGen). It demonstrated a superior capacity to generate unique molecules, exhibited greater structural similarity to approved drugs, and achieved improved predicted binding affinities across all targets. Molecular docking analyses further supported these findings, identifying candidate ligands with strong binding potential, including compounds with predicted affinities (-9.917, -9.485, and -9.367) exceeding those of reference drugs such as enalapril for angiotensin-converting enzyme (-8.283). By integrating disease-specific context into molecular generation, DrugGen-2 advances AI-assisted drug discovery, offering a powerful tool for de novo design and drug repurposing that accounts for the complex interplay between diseases and molecular targets.

The recent advances in neural language models have also been successfully applied to the field of chemistry, offering generative solutions for classical problems in molecular design and synthesis planning. These new methods have the potential to optimize laboratory operations and fuel a new era of data-driven automation in scientific discovery. However, specialized models are still typically required for each task, leading to the need for problem-specific fine-tuning and neglecting task interrelations. The main obstacle in this field is the lack of a unified representation between natural language and chemical representations, complicating and limiting human-machine interaction. Here, we propose a multi-domain, multi-task language model to solve a wide range of tasks in both the chemical and natural language domains. By leveraging multi-task learning, our model can handle chemical and natural language concurrently, without requiring expensive pre-training on single domains or task-specific models. Interestingly, sharing weights across domains remarkably improves our model when benchmarked against state-of-the-art baselines on single-domain and cross-domain tasks. In particular, sharing information across domains and tasks gives rise to large improvements in cross-domain tasks, the magnitude of which increase with scale, as measured by more than a dozen of relevant metrics. Our work suggests that such models can robustly and efficiently accelerate discovery in physical sciences by superseding problem-specific fine-tuning and enhancing human-model interactions.

Molecular "fingerprints" encoding structural information are the workhorse of cheminformatics and machine learning in drug discovery applications. However, fingerprint representations necessarily emphasize particular aspects of the molecular structure while ignoring others, rather than allowing the model to make data-driven decisions. We describe molecular "graph convolutions", a machine learning architecture for learning from undirected graphs, specifically small molecules. Graph convolutions use a simple encoding of the molecular graph---atoms, bonds, distances, etc.---which allows the model to take greater advantage of information in the graph structure. Although graph convolutions do not outperform all fingerprint-based methods, they (along with other graph-based methods) represent a new paradigm in ligand-based virtual screening with exciting opportunities for future improvement.

We report a series of deep learning models to solve complex forward and inverse design problems in molecular modeling and design. Using both diffusion models inspired by nonequilibrium thermodynamics and attention-based transformer architectures, we demonstrate a flexible framework to capture complex chemical structures. First trained on the QM9 dataset and a series of quantum mechanical properties (e.g. homo, lumo, free energy, heat capacity, etc.), we then generalize the model to study and design key properties of deep eutectic solvents. In addition to separate forward and inverse models, we also report an integrated fully prompt-based multi-task generative pretrained transformer model that solves multiple forward, inverse design, and prediction tasks, flexibly and within one model. We show that the multi-task generative model has the overall best performance and allows for flexible integration of multiple objectives, within one model, and for distinct chemistries, suggesting that synergies emerge during training of this large language model. Trained jointly in tasks related to the QM9 dataset and deep eutectic solvents (DESs), the model can predict various quantum mechanical properties and critical properties to achieve deep eutectic solvent behavior. Several novel combinations of DESs are proposed based on this framework.

Efficient molecular modeling and design are crucial for the discovery and exploration of novel molecules, and the incorporation of deep learning methods has revolutionized this field. In particular, large language models (LLMs) offer a fresh approach to tackle scientific problems from a natural language processing (NLP) perspective, introducing a research paradigm called scientific language modeling (SLM). However, two key issues remain: how to quantify the match between model and data modalities and how to identify the knowledge-learning preferences of models. To address these challenges, we propose a multi-modal benchmark, named ChEBI-20-MM, and perform 1263 experiments to assess the model's compatibility with data modalities and knowledge acquisition. Through the modal transition probability matrix, we provide insights into the most suitable modalities for tasks. Furthermore, we introduce a statistically interpretable approach to discover context-specific knowledge mapping by localized feature filtering. Our pioneering analysis offers an exploration of the learning mechanism and paves the way for advancing SLM in molecular science.

Molecular Representation Learning (MRL) has proven impactful in numerous biochemical applications such as drug discovery and enzyme design. While Graph Neural Networks (GNNs) are effective at learning molecular representations from a 2D molecular graph or a single 3D structure, existing works often overlook the flexible nature of molecules, which continuously interconvert across conformations via chemical bond rotations and minor vibrational perturbations. To better account for molecular flexibility, some recent works formulate MRL as an ensemble learning problem, focusing on explicitly learning from a set of conformer structures. However, most of these studies have limited datasets, tasks, and models. In this work, we introduce the first MoleculAR Conformer Ensemble Learning (MARCEL) benchmark to thoroughly evaluate the potential of learning on conformer ensembles and suggest promising research directions. MARCEL includes four datasets covering diverse molecule- and reaction-level properties of chemically diverse molecules including organocatalysts and transition-metal catalysts, extending beyond the scope of common GNN benchmarks that are confined to drug-like molecules. In addition, we conduct a comprehensive empirical study, which benchmarks representative 1D, 2D, and 3D molecular representation learning models, along with two strategies that explicitly incorporate conformer ensembles into 3D MRL models. Our findings reveal that direct learning from an accessible conformer space can improve performance on a variety of tasks and models.

While molecular pre-training has shown great potential in enhancing drug discovery, the lack of a solid physical interpretation in current methods raises concerns about whether the learned representation truly captures the underlying explanatory factors in observed data, ultimately resulting in limited generalization and robustness. Although denoising methods offer a physical interpretation, their accuracy is often compromised by ad-hoc noise design, leading to inaccurate learned force fields. To address this limitation, this paper proposes a new method for molecular pre-training, called sliced denoising (SliDe), which is based on the classical mechanical intramolecular potential theory. SliDe utilizes a novel noise strategy that perturbs bond lengths, angles, and torsion angles to achieve better sampling over conformations. Additionally, it introduces a random slicing approach that circumvents the computationally expensive calculation of the Jacobian matrix, which is otherwise essential for estimating the force field. By aligning with physical principles, SliDe shows a 42\% improvement in the accuracy of estimated force fields compared to current state-of-the-art denoising methods, and thus outperforms traditional baselines on various molecular property prediction tasks.

Fragment-based drug discovery has been an effective paradigm in early-stage drug development. An open challenge in this area is designing linkers between disconnected molecular fragments of interest to obtain chemically-relevant candidate drug molecules. In this work, we propose DiffLinker, an E(3)-equivariant 3D-conditional diffusion model for molecular linker design. Given a set of disconnected fragments, our model places missing atoms in between and designs a molecule incorporating all the initial fragments. Unlike previous approaches that are only able to connect pairs of molecular fragments, our method can link an arbitrary number of fragments. Additionally, the model automatically determines the number of atoms in the linker and its attachment points to the input fragments. We demonstrate that DiffLinker outperforms other methods on the standard datasets generating more diverse and synthetically-accessible molecules. Besides, we experimentally test our method in real-world applications, showing that it can successfully generate valid linkers conditioned on target protein pockets.

Finding new drugs is getting harder and harder. One of the hopes of drug discovery is to use machine learning models to predict molecular properties. That is why models for molecular property prediction are being developed and tested on benchmarks such as MoleculeNet. However, existing benchmarks are unrealistic and are too different from applying the models in practice. We have created a new practical Lo-Hi benchmark consisting of two tasks: Lead Optimization (Lo) and Hit Identification (Hi), corresponding to the real drug discovery process. For the Hi task, we designed a novel molecular splitting algorithm that solves the Balanced Vertex Minimum k-Cut problem. We tested state-of-the-art and classic ML models, revealing which works better under practical settings. We analyzed modern benchmarks and showed that they are unrealistic and overoptimistic. Review: https://openreview.net/forum?id=H2Yb28qGLV Lo-Hi benchmark: https://github.com/SteshinSS/lohi_neurips2023 Lo-Hi splitter library: https://github.com/SteshinSS/lohi_splitter

Molecular generation with diffusion models has emerged as a promising direction for AI-driven drug discovery and materials science. While graph diffusion models have been widely adopted due to the discrete nature of 2D molecular graphs, existing models suffer from low chemical validity and struggle to meet the desired properties compared to 1D modeling. In this work, we introduce MolHIT, a powerful molecular graph generation framework that overcomes long-standing performance limitations in existing methods. MolHIT is based on the Hierarchical Discrete Diffusion Model, which generalizes discrete diffusion to additional categories that encode chemical priors, and decoupled atom encoding that splits the atom types according to their chemical roles. Overall, MolHIT achieves new state-of-the-art performance on the MOSES dataset with near-perfect validity for the first time in graph diffusion, surpassing strong 1D baselines across multiple metrics. We further demonstrate strong performance in downstream tasks, including multi-property guided generation and scaffold extension.

General-purpose large language models (LLMs) that rely on in-context learning do not reliably deliver the scientific understanding and performance required for drug discovery tasks. Simply increasing model size or introducing reasoning tokens does not yield significant performance gains. To address this gap, we introduce the MMAI Gym for Science, a one-stop shop molecular data formats and modalities as well as task-specific reasoning, training, and benchmarking recipes designed to teach foundation models the 'language of molecules' in order to solve practical drug discovery problems. We use MMAI Gym to train an efficient Liquid Foundation Model (LFM) for these applications, demonstrating that smaller, purpose-trained foundation models can outperform substantially larger general-purpose or specialist models on molecular benchmarks. Across essential drug discovery tasks - including molecular optimization, ADMET property prediction, retrosynthesis, drug-target activity prediction, and functional group reasoning - the resulting model achieves near specialist-level performance and, in the majority of settings, surpasses larger models, while remaining more efficient and broadly applicable in the domain.

Generative models hold great promise for small molecule discovery, significantly increasing the size of search space compared to traditional in silico screening libraries. However, most existing machine learning methods for small molecule generation suffer from poor synthesizability of candidate compounds, making experimental validation difficult. In this paper we propose Reaction-GFlowNet (RGFN), an extension of the GFlowNet framework that operates directly in the space of chemical reactions, thereby allowing out-of-the-box synthesizability while maintaining comparable quality of generated candidates. We demonstrate that with the proposed set of reactions and building blocks, it is possible to obtain a search space of molecules orders of magnitude larger than existing screening libraries coupled with low cost of synthesis. We also show that the approach scales to very large fragment libraries, further increasing the number of potential molecules. We demonstrate the effectiveness of the proposed approach across a range of oracle models, including pretrained proxy models and GPU-accelerated docking.

The widespread application of Artificial Intelligence (AI) techniques has significantly influenced the development of new therapeutic agents. These computational methods can be used to design and predict the properties of generated molecules. Multi-target Drug Discovery (MTDD) is an emerging paradigm for discovering drugs against complex disorders that do not respond well to more traditional target-specific treatments, such as central nervous system, immune system, and cardiovascular diseases. Still, there is yet to be an established benchmark suite for assessing the effectiveness of AI tools for designing multi-target compounds. Standardized benchmarks allow for comparing existing techniques and promote rapid research progress. Hence, this work proposes an evaluation framework for molecule generation techniques in MTDD scenarios, considering brain diseases as a case study. Our methodology involves using large language models to select the appropriate molecular targets, gathering and preprocessing the bioassay datasets, training quantitative structure-activity relationship models to predict target modulation, and assessing other essential drug-likeness properties for implementing the benchmarks. Additionally, this work will assess the performance of four deep generative models and evolutionary algorithms over our benchmark suite. In our findings, both evolutionary algorithms and generative models can achieve competitive results across the proposed benchmarks.

Graph neural networks (GNNs) have been used extensively for addressing problems in drug design and discovery. Both ligand and target molecules are represented as graphs with node and edge features encoding information about atomic elements and bonds respectively. Although existing deep learning models perform remarkably well at predicting physicochemical properties and binding affinities, the generation of new molecules with optimized properties remains challenging. Inherently, most GNNs perform poorly in whole-graph representation due to the limitations of the message-passing paradigm. Furthermore, step-by-step graph generation frameworks that use reinforcement learning or other sequential processing can be slow and result in a high proportion of invalid molecules with substantial post-processing needed in order to satisfy the principles of stoichiometry. To address these issues, we propose a representation-first approach to molecular graph generation. We guide the latent representation of an autoencoder by capturing graph structure information with the geometric scattering transform and apply penalties that structure the representation also by molecular properties. We show that this highly structured latent space can be directly used for molecular graph generation by the use of a GAN. We demonstrate that our architecture learns meaningful representations of drug datasets and provides a platform for goal-directed drug synthesis.

Property prediction plays an important role in material discovery. As an initial step to eventually develop a foundation model for material science, we introduce a new autoencoder called the MHG-GNN, which combines graph neural network (GNN) with Molecular Hypergraph Grammar (MHG). Results on a variety of property prediction tasks with diverse materials show that MHG-GNN is promising.

The discovery and identification of molecules in biological and environmental samples is crucial for advancing biomedical and chemical sciences. Tandem mass spectrometry (MS/MS) is the leading technique for high-throughput elucidation of molecular structures. However, decoding a molecular structure from its mass spectrum is exceptionally challenging, even when performed by human experts. As a result, the vast majority of acquired MS/MS spectra remain uninterpreted, thereby limiting our understanding of the underlying (bio)chemical processes. Despite decades of progress in machine learning applications for predicting molecular structures from MS/MS spectra, the development of new methods is severely hindered by the lack of standard datasets and evaluation protocols. To address this problem, we propose MassSpecGym -- the first comprehensive benchmark for the discovery and identification of molecules from MS/MS data. Our benchmark comprises the largest publicly available collection of high-quality labeled MS/MS spectra and defines three MS/MS annotation challenges: de novo molecular structure generation, molecule retrieval, and spectrum simulation. It includes new evaluation metrics and a generalization-demanding data split, therefore standardizing the MS/MS annotation tasks and rendering the problem accessible to the broad machine learning community. MassSpecGym is publicly available at https://github.com/pluskal-lab/MassSpecGym.

Drug discovery is a complex process that involves multiple scenarios and stages, such as fragment-constrained molecule generation, hit generation and lead optimization. However, existing molecular generative models can only tackle one or two of these scenarios and lack the flexibility to address various aspects of the drug discovery pipeline. In this paper, we present Generalist Molecular generative model (GenMol), a versatile framework that addresses these limitations by applying discrete diffusion to the Sequential Attachment-based Fragment Embedding (SAFE) molecular representation. GenMol generates SAFE sequences through non-autoregressive bidirectional parallel decoding, thereby allowing utilization of a molecular context that does not rely on the specific token ordering and enhanced computational efficiency. Moreover, under the discrete diffusion framework, we introduce fragment remasking, a strategy that optimizes molecules by replacing fragments with masked tokens and regenerating them, enabling effective exploration of chemical space. GenMol significantly outperforms the previous GPT-based model trained on SAFE representations in de novo generation and fragment-constrained generation, and achieves state-of-the-art performance in goal-directed hit generation and lead optimization. These experimental results demonstrate that GenMol can tackle a wide range of drug discovery tasks, providing a unified and versatile approach for molecular design.

The central molecular zone (CMZ) of our Galaxy exhibits widespread emission from SiO and various complex organic molecules (COMs), yet the exact origin of such emission is uncertain. Here we report the discovery of a unique class of long (>0.5 pc) and narrow (<0.03 pc) filaments in the emission of SiO 5-4 and eight additional molecular lines, including several COMs, in our ALMA 1.3 mm spectral line observations toward two massive molecular clouds in the CMZ, which we name as slim filaments. However, these filaments are not detected in the 1.3 mm continuum at the 5sigma level. Their line-of-sight velocities are coherent and inconsistent with being outflows. The column densities and relative abundances of the detected molecules are statistically similar to those in protostellar outflows but different from those in dense cores within the same clouds. Turbulent pressure in these filaments dominates over self gravity and leads to hydrostatic inequilibrium, indicating that they are a different class of objects than the dense gas filaments in dynamical equilibrium ubiquitously found in nearby molecular clouds. We argue that these newly detected slim filaments are associated with parsec-scale shocks, likely arising from dynamic interactions between shock waves and molecular clouds. The dissipation of the slim filaments may replenish SiO and COMs in the interstellar medium and lead to their widespread emission in the CMZ.

Understanding the chemical structure from a graphical representation of a molecule is a challenging image caption task that would greatly benefit molecule-centric scientific discovery. Variations in molecular images and caption subtasks pose a significant challenge in both image representation learning and task modeling. Yet, existing methods only focus on a specific caption task that translates a molecular image into its graph structure, i.e., OCSR. In this paper, we propose the Optical Chemical Structure Understanding (OCSU) task, which extends OCSR to molecular image caption from motif level to molecule level and abstract level. We present two approaches for that, including an OCSR-based method and an end-to-end OCSR-free method. The proposed Double-Check achieves SOTA OCSR performance on real-world patent and journal article scenarios via attentive feature enhancement for local ambiguous atoms. Cascading with SMILES-based molecule understanding methods, it can leverage the power of existing task-specific models for OCSU. While Mol-VL is an end-to-end optimized VLM-based model. An OCSU dataset, Vis-CheBI20, is built based on the widely used CheBI20 dataset for training and evaluation. Extensive experimental results on Vis-CheBI20 demonstrate the effectiveness of the proposed approaches. Improving OCSR capability can lead to a better OCSU performance for OCSR-based approach, and the SOTA performance of Mol-VL demonstrates the great potential of end-to-end approach.

3D molecule generation is crucial for drug discovery and material science, requiring models to process complex multi-modalities, including atom types, chemical bonds, and 3D coordinates. A key challenge is integrating these modalities of different shapes while maintaining SE(3) equivariance for 3D coordinates. To achieve this, existing approaches typically maintain separate latent spaces for invariant and equivariant modalities, reducing efficiency in both training and sampling. In this work, we propose Unified Variational Auto-Encoder for 3D Molecular Latent Diffusion Modeling (UAE-3D), a multi-modal VAE that compresses 3D molecules into latent sequences from a unified latent space, while maintaining near-zero reconstruction error. This unified latent space eliminates the complexities of handling multi-modality and equivariance when performing latent diffusion modeling. We demonstrate this by employing the Diffusion Transformer--a general-purpose diffusion model without any molecular inductive bias--for latent generation. Extensive experiments on GEOM-Drugs and QM9 datasets demonstrate that our method significantly establishes new benchmarks in both de novo and conditional 3D molecule generation, achieving leading efficiency and quality.

Molecular pretrained representations (MPR) has emerged as a powerful approach for addressing the challenge of limited supervised data in applications such as drug discovery and material design. While early MPR methods relied on 1D sequences and 2D graphs, recent advancements have incorporated 3D conformational information to capture rich atomic interactions. However, these prior models treat molecules merely as discrete atom sets, overlooking the space surrounding them. We argue from a physical perspective that only modeling these discrete points is insufficient. We first present a simple yet insightful observation: naively adding randomly sampled virtual points beyond atoms can surprisingly enhance MPR performance. In light of this, we propose a principled framework that incorporates the entire 3D space spanned by molecules. We implement the framework via a novel Transformer-based architecture, dubbed SpaceFormer, with three key components: (1) grid-based space discretization; (2) grid sampling/merging; and (3) efficient 3D positional encoding. Extensive experiments show that SpaceFormer significantly outperforms previous 3D MPR models across various downstream tasks with limited data, validating the benefit of leveraging the additional 3D space beyond atoms in MPR models.

Text-based foundation models have become an important part of scientific discovery, with molecular foundation models accelerating advancements in material science and molecular design.However, existing models are constrained by closed-vocabulary tokenizers that capture only a fraction of molecular space. In this work, we systematically evaluate 34 tokenizers, including 19 chemistry-specific ones, and reveal significant gaps in their coverage of the SMILES molecular representation. To assess the impact of tokenizer choice, we introduce n-gram language models as a low-cost proxy and validate their effectiveness by pretraining and finetuning 18 RoBERTa-style encoders for molecular property prediction. To overcome the limitations of existing tokenizers, we propose two new tokenizers -- Smirk and Smirk-GPE -- with full coverage of the OpenSMILES specification. The proposed tokenizers systematically integrate nuclear, electronic, and geometric degrees of freedom; facilitating applications in pharmacology, agriculture, biology, and energy storage. Our results highlight the need for open-vocabulary modeling and chemically diverse benchmarks in cheminformatics.

Generating new molecules is fundamental to advancing critical applications such as drug discovery and material synthesis. Flows can generate molecules effectively by inverting the encoding process, however, existing flow models either require artifactual dequantization or specific node/edge orderings, lack desiderata such as permutation invariance, or induce discrepancy between the encoding and the decoding steps that necessitates post hoc validity correction. We circumvent these issues with novel continuous normalizing E(3)-equivariant flows, based on a system of node ODEs coupled as a graph PDE, that repeatedly reconcile locally toward globally aligned densities. Our models can be cast as message-passing temporal networks, and result in superlative performance on the tasks of density estimation and molecular generation. In particular, our generated samples achieve state-of-the-art on both the standard QM9 and ZINC250K benchmarks.

Accurate prediction of atomistic, thermodynamic, and kinetic properties from molecular structures underpins materials innovation. Existing computational and experimental approaches lack the scalability required to efficiently navigate chemical space. Scientific foundation models trained on large unlabeled datasets offer a path toward exploring chemical space across diverse application domains. Here we develop MIST, a family of molecular foundation models with up to an order of magnitude more parameters and data than prior works. Trained using a novel tokenization scheme that comprehensively captures nuclear, electronic, and geometric information, MIST learns from a diverse range of molecules. MIST models have been fine-tuned to predict more than 400 structure -- property relationships and match or exceed state-of-the-art performance across benchmarks spanning physiology, electrochemistry, and quantum chemistry. We demonstrate the ability of these models to solve real-world problems across chemical space, including multiobjective electrolyte solvent screening, olfactory perception mapping, isotope half-life prediction, stereochemical reasoning for chiral organometallic compounds, and binary and multi-component mixture property prediction. Probing MIST models using mechanistic interpretability methods reveals identifiable patterns and trends not explicitly present in the training data, suggesting that the models learn generalizable scientific concepts. We formulate hyperparameter-penalized Bayesian neural scaling laws and use them to reduce the computational cost of model development by an order of magnitude. The methods and findings presented here represent a significant step toward accelerating materials discovery, design, and optimization using foundation models and provide valuable guidance for training compute-optimal scientific foundation models.

Cancer is known as a disease mainly caused by gene alterations. Discovery of mutated driver pathways or gene sets is becoming an important step to understand molecular mechanisms of carcinogenesis. However, systematically investigating commonalities and specificities of driver gene sets among multiple cancer types is still a great challenge, but this investigation will undoubtedly benefit deciphering cancers and will be helpful for personalized therapy and precision medicine in cancer treatment. In this study, we propose two optimization models to de novo discover common driver gene sets among multiple cancer types (ComMDP) and specific driver gene sets of one certain or multiple cancer types to other cancers (SpeMDP), respectively. We first apply ComMDP and SpeMDP to simulated data to validate their efficiency. Then, we further apply these methods to 12 cancer types from The Cancer Genome Atlas (TCGA) and obtain several biologically meaningful driver pathways. As examples, we construct a common cancer pathway model for BRCA and OV, infer a complex driver pathway model for BRCA carcinogenesis based on common driver gene sets of BRCA with eight cancer types, and investigate specific driver pathways of the liquid cancer lymphoblastic acute myeloid leukemia (LAML) versus other solid cancer types. In these processes more candidate cancer genes are also found.

Deep learning models facilitate the discovery of molecules with tailored properties among billions of candidate compounds. However, the computational burden to develop and deploy state-of-the-art models continuously increases, limiting their scalability. Most large-scale models are unimodal in nature and overlook the potential to leverage complementary molecular data modalities. To address these shortcomings, this paper introduces the Graph-Language Alignment for Chemical Inference and Exploration using Representations (GLACIER) model, a student-teacher framework that integrates molecular graphs, SMILES strings, and physicochemical descriptors to learn rich molecular embeddings. Our framework consists of three stages: (1) we pretrain three student encoders on 100,000 drug-like molecules: a message-passing neural network for molecular graphs, a transformer-based encoder for SMILES strings, and a multilayer perceptron for physicochemical descriptors, (2) we fuse these student modalities using a novel Finsler geometry-aware module, and (3) distill complementary knowledge from large teacher models, including MiniMol and MolFormer, into a single lightweight model via contrastive learning. We demonstrate that GLACIER is a robust framework that delivers high predictive performance and computational efficiency in complex molecular property prediction tasks. Our code is publicly available at https://github.com/eemokey/glacier.

Continuous physical fields represent a large fraction of data under scientific investigation. Their multiscale structures are central to discovery, yet useful coordinates are not known in advance. Standard self-supervised methods define context and targets in fixed image coordinates, posing a predictive task misaligned with fields organized across a continuous scale hierarchy. We introduce ScaleAware-JEPA, a framework that constructs dense, label-free latent coordinates for continuous scalar fields. Constrained Diffusion Decomposition (CDD) separates each field into pixel-registered scale components and provides the scale coordinates that define the masking geometry. The resulting JEPA objective predicts hidden structure with a context footprint tied to the diffusion scale of each component rather than to an arbitrary patch size. Across MHD turbulence, interstellar molecular gas and urban nighttime-light structure, the learned geometry maps back to coherent morphology, forming dense structural atlases without labels or predefined segmentation rules. By tying latent prediction to the scale hierarchy of a field, ScaleAware-JEPA constructs latent coordinates through which complex physical patterns can be inspected before their relevant structures have been prescribed. Code is available at https://github.com/gxli/SA-JEPA.

In this paper, we review recent developments and the role of Graph Neural Networks (GNNs) in computational drug discovery, including molecule generation, molecular property prediction, and drug-drug interaction prediction. By summarizing the most recent developments in this area, we underscore the capabilities of GNNs to comprehend intricate molecular patterns, while exploring both their current and prospective applications. We initiate our discussion by examining various molecular representations, followed by detailed discussions and categorization of existing GNN models based on their input types and downstream application tasks. We also collect a list of commonly used benchmark datasets for a variety of applications. We conclude the paper with brief discussions and summarize common trends in this important research area.

Inverse molecular design with diffusion models holds great potential for advancements in material and drug discovery. Despite success in unconditional molecular generation, integrating multiple properties such as synthetic score and gas permeability as condition constraints into diffusion models remains unexplored. We present the Graph Diffusion Transformer (Graph DiT) for multi-conditional molecular generation. Graph DiT integrates an encoder to learn numerical and categorical property representations with the Transformer-based denoiser. Unlike previous graph diffusion models that add noise separately on the atoms and bonds in the forward diffusion process, Graph DiT is trained with a novel graph-dependent noise model for accurate estimation of graph-related noise in molecules. We extensively validate Graph DiT for multi-conditional polymer and small molecule generation. Results demonstrate the superiority of Graph DiT across nine metrics from distribution learning to condition control for molecular properties. A polymer inverse design task for gas separation with feedback from domain experts further demonstrates its practical utility.

Automated computational analysis of the vast chemical space is critical for numerous fields of research such as drug discovery and material science. Representation learning techniques have recently been employed with the primary objective of generating compact and informative numerical expressions of complex data. One approach to efficiently learn molecular representations is processing string-based notations of chemicals via natural language processing (NLP) algorithms. Majority of the methods proposed so far utilize SMILES notations for this purpose; however, SMILES is associated with numerous problems related to validity and robustness, which may prevent the model from effectively uncovering the knowledge hidden in the data. In this study, we propose SELFormer, a transformer architecture-based chemical language model that utilizes a 100% valid, compact and expressive notation, SELFIES, as input, in order to learn flexible and high-quality molecular representations. SELFormer is pre-trained on two million drug-like compounds and fine-tuned for diverse molecular property prediction tasks. Our performance evaluation has revealed that, SELFormer outperforms all competing methods, including graph learning-based approaches and SMILES-based chemical language models, on predicting aqueous solubility of molecules and adverse drug reactions. We also visualized molecular representations learned by SELFormer via dimensionality reduction, which indicated that even the pre-trained model can discriminate molecules with differing structural properties. We shared SELFormer as a programmatic tool, together with its datasets and pre-trained models. Overall, our research demonstrates the benefit of using the SELFIES notations in the context of chemical language modeling and opens up new possibilities for the design and discovery of novel drug candidates with desired features.

The success of drug discovery and development relies on the precise prediction of molecular activities and properties. While in silico molecular property prediction has shown remarkable potential, its use has been limited so far to assays for which large amounts of data are available. In this study, we use a fine-tuned large language model to integrate biological assays based on their textual information, coupled with Barlow Twins, a Siamese neural network using a novel self-supervised learning approach. This architecture uses both assay information and molecular fingerprints to extract the true molecular information. TwinBooster enables the prediction of properties of unseen bioassays and molecules by providing state-of-the-art zero-shot learning tasks. Remarkably, our artificial intelligence pipeline shows excellent performance on the FS-Mol benchmark. This breakthrough demonstrates the application of deep learning to critical property prediction tasks where data is typically scarce. By accelerating the early identification of active molecules in drug discovery and development, this method has the potential to help streamline the identification of novel therapeutics.

Superconductivity allows electrical current to flow without any energy loss, and thus making solids superconducting is a grand goal of physics, material science, and electrical engineering. More than 16 Nobel Laureates have been awarded for their contribution to superconductivity research. Superconductors are valuable for sustainable development goals (SDGs), such as climate change mitigation, affordable and clean energy, industry, innovation and infrastructure, and so on. However, a unified physics theory explaining all superconductivity mechanism is still unknown. It is believed that superconductivity is microscopically due to not only molecular compositions but also the geometric crystal structure. Hence a new dataset, S2S, containing both crystal structures and superconducting critical temperature, is built upon SuperCon and Material Project. Based on this new dataset, we propose a novel model, S2SNet, which utilizes the attention mechanism for superconductivity prediction. To overcome the shortage of data, S2SNet is pre-trained on the whole Material Project dataset with Masked-Language Modeling (MLM). S2SNet makes a new state-of-the-art, with out-of-sample accuracy of 92% and Area Under Curve (AUC) of 0.92. To the best of our knowledge, S2SNet is the first work to predict superconductivity with only information of crystal structures. This work is beneficial to superconductivity discovery and further SDGs. Code and datasets are available in https://github.com/zjuKeLiu/S2SNet

There will be a paradigm shift in chemical and biological research, to be enabled by autonomous, closed-loop, real-time self-directed decision-making experimentation. Spectrum-to-structure correlation, which is to elucidate molecular structures with spectral information, is the core step in understanding the experimental results and to close the loop. However, current approaches usually divide the task into either database-dependent retrieval and database-independent generation and neglect the inherent complementarity between them. In this study, we proposed Vib2Mol, a general deep learning model designed to flexibly handle diverse spectrum-to-structure tasks according to the available prior knowledge by bridging the retrieval and generation. It achieves state-of-the-art performance, even for the most demanding Raman spectra, over previous models in predicting reaction products and sequencing peptides as well as analyzing experimental spectra and integrating multi-modal spectral data. Vib2Mol enables vibrational spectroscopy a real-time guide for autonomous scientific discovery workflows.

The nexus of quantum computing and machine learning - quantum machine learning - offers the potential for significant advancements in chemistry. This review specifically explores the potential of quantum neural networks on gate-based quantum computers within the context of drug discovery. We discuss the theoretical foundations of quantum machine learning, including data encoding, variational quantum circuits, and hybrid quantum-classical approaches. Applications to drug discovery are highlighted, including molecular property prediction and molecular generation. We provide a balanced perspective, emphasizing both the potential benefits and the challenges that must be addressed.

Small molecules are essential to drug discovery, and graph-language models hold promise for learning molecular properties and functions from text. However, existing molecule-text datasets are limited in scale and informativeness, restricting the training of generalizable multimodal models. We present MolTextNet, a dataset of 2.5 million high-quality molecule-text pairs designed to overcome these limitations. To construct it, we propose a synthetic text generation pipeline that integrates structural features, computed properties, bioactivity data, and synthetic complexity. Using GPT-4o-mini, we create structured descriptions for 2.5 million molecules from ChEMBL35, with text over 10 times longer than prior datasets. MolTextNet supports diverse downstream tasks, including property prediction and structure retrieval. Pretraining CLIP-style models with Graph Neural Networks and ModernBERT on MolTextNet yields improved performance, highlighting its potential for advancing foundational multimodal modeling in molecular science. Our dataset is available at https://huggingface.co/datasets/liuganghuggingface/moltextnet.

Conformational ensembles of protein structures are immensely important both for understanding protein function and drug discovery in novel modalities such as cryptic pockets. Current techniques for sampling ensembles such as molecular dynamics (MD) are computationally inefficient, while many recent machine learning methods do not transfer to systems outside their training data. We propose JAMUN which performs MD in a smoothed, noised space of all-atom 3D conformations of molecules by utilizing the framework of walk-jump sampling. JAMUN enables ensemble generation for small peptides at rates of an order of magnitude faster than traditional molecular dynamics. The physical priors in JAMUN enables transferability to systems outside of its training data, even to peptides that are longer than those originally trained on. Our model, code and weights are available at https://github.com/prescient-design/jamun.

Docking is a crucial component in drug discovery aimed at predicting the binding conformation and affinity between small molecules and target proteins. ML-based docking has recently emerged as a prominent approach, outpacing traditional methods like DOCK and AutoDock Vina in handling the growing scale and complexity of molecular libraries. However, the availability of comprehensive and user-friendly datasets for training and benchmarking ML-based docking algorithms remains limited. We introduce Smiles2Dock, an open large-scale multi-task dataset for molecular docking. We created a framework combining P2Rank and AutoDock Vina to dock 1.7 million ligands from the ChEMBL database against 15 AlphaFold proteins, giving us more than 25 million protein-ligand binding scores. The dataset leverages a wide range of high-accuracy AlphaFold protein models, encompasses a diverse set of biologically relevant compounds and enables researchers to benchmark all major approaches for ML-based docking such as Graph, Transformer and CNN-based methods. We also introduce a novel Transformer-based architecture for docking scores prediction and set it as an initial benchmark for our dataset. Our dataset and code are publicly available to support the development of novel ML-based methods for molecular docking to advance scientific research in this field.

Molecules play a crucial role in biomedical research and discovery, particularly in the field of small molecule drug development. Given the rapid advancements in large language models, especially the recent emergence of reasoning models, it is natural to explore how a general-purpose language model can be efficiently adapted for molecular science applications. In this work, we introduce BioMedGPT-Mol, a molecular language model designed to support molecular understanding and generation tasks. By curating and unifying existing public instruction datasets, we have assembled a large-scale, comprehensive, and high-quality training dataset. The model is then fine-tuned through a meticulously designed multi-task learning framework. On a consolidated benchmark derived from LlaSMol, TOMG-Bench, and MuMOInstruct, BioMedGPT-Mol achieves remarkable performance. Our experimental results demonstrate that a general-purpose reasoning model can be effectively and efficiently post-trained into a professional molecular language model through a well-structured multi-task curriculum. Leveraging these capabilities, we further apply the model to multi-step retrosynthetic planning, achieving state-of-the-art performance on RetroBench and demonstrating its superior efficacy as an end-to-end retrosynthetic planner. We anticipate that our approach can be extended to other biomedical scientific domains.

Causal representation learning (CRL) seeks to recover latent variables with identifiability guarantees, typically up to permutation and component-wise reparameterization under appropriate assumptions. However, identifiability does not imply interpretability: latent semantics are typically assigned post hoc by alignment with known ground-truth factors. This limitation is particularly acute in scientific time series, where underlying mechanisms are unknown and discovering interpretable structure is a primary goal. In contrast, scientific observations (such as residue-pair distances, climate indices, or process sensors) are inherently semantic, as they correspond to named physical quantities. This raises a key question: can the interpretability of observations be transferred to the identifiable latent space? We propose MOSAIC (Module discovery via Sparse Additive Identifiable Causal learning), a sparse temporal VAE that integrates temporal CRL identifiability with support recovery over observed variables. MOSAIC identifies latent variables via regime-conditioned temporal variation, and recovers for each latent a sparse set of associated observations through an additive decoder, yielding module-level interpretability. We show that ANOVA main-effect supports are identifiable under general smooth mixing functions, and provide finite-sample recovery guarantees for a tractable sparse-additive variant. Empirically, MOSAIC recovers domain-consistent variable groups across RNA molecular dynamics, solar wind, ENSO climate, the Tennessee Eastman process, and a synthetic tokamak benchmark, enabling interpretable discovery of latent mechanisms in scientific time series.

Scientific discovery often involves optimising expensive-to-evaluate objectives over vast, structured, and open-ended hypothesis spaces, such as molecules, protein sequences, and computer programs. Generative models such as large language models (LLMs) provide expressive priors over such spaces, but their likelihoods and self-assessments are unreliable proxies for the objectives and calibrated epistemic uncertainty, especially for novel candidates outside the observed data distribution. We introduce the Large Discovery Model (LDM), an empirically grounded recurrent architecture that couples a generative model with a Bayesian non-parametric reward surrogate model. The generative model proposes and refines candidate designs, while the surrogate predicts their performance and quantifies uncertainty, yielding an uncertainty-aware value that guides candidate generation, refinement, and selection. The discovery memory and the surrogate model are continually updated as each new experimental observation arrives. We evaluate LDM on three scenarios spanning different design modalities and objectives, including neural-network training, antibody design, and molecular optimisation. Compared to LLM-only reflection or traditional statistical search across these domains, LDM achieves a 2.4times greater reduction in validation BPB, an 18.2% relative decrease in binding energy, and more than 60% relative gains in molecular multi-objective performance. These results suggests that LDM could serve as a general-purpose discovery engine for effective search over open-ended hypothesis spaces.

Recent advancements have integrated Language Models (LMs) into a drug discovery pipeline. However, existing models mostly work with SMILES and SELFIES chemical string representations, which lack spatial features vital for drug discovery. Additionally, attempts to translate chemical 3D structures into text format encounter issues such as excessive length and insufficient atom connectivity information. To address these issues, we introduce nach0-pc, a model combining domain-specific encoder and textual representation to handle spatial arrangement of atoms effectively. Our approach utilizes a molecular point cloud encoder for concise and order-invariant structure representation. We introduce a novel pre-training scheme for molecular point clouds to distillate the knowledge from spatial molecular structures datasets. After fine-tuning within both single-task and multi-task frameworks, nach0-pc demonstrates performance comparable with other diffusion models in terms of generated samples quality across several established spatial molecular generation tasks. Notably, our model is a multi-task approach, in contrast to diffusion models being limited to single tasks. Additionally, it is capable of processing point cloud-related data, which language models are not capable of handling due to memory limitations. These lead to our model having reduced training and inference time while maintaining on par performance.

The growing sophistication of drug discovery calls for new advances in artificial intelligence (AI). Transformers have underpinned recent breakthroughs in AI, yet their conventional source-target attention mechanism can become a bottleneck for modeling complex interactions. Here, we introduce TopoLIA, a topology-inspired latent interaction attention mechanism that learns not only how much information should be exchanged between interaction partners, but also how that information should be transformed. Source-target-dependent attention is mediated through a compact latent interaction space, providing a structured representation of complex interactions. We further incorporate topological spectral representations to capture multiscale data geometry and extract algebraic relationships. TopoLIA thus incorporates topological principles into both data representation and neural network architecture. We demonstrate TopoLIA on protein-ligand binding, where persistent spectra encode multiscale topological and geometric patterns in 3D protein-ligand complexes, while latent interaction attention (LIA) enables structured, source-target-dependent information exchange. We pretrain TopoLIA by reconstructing masked multiscale spectral tokens from unlabeled molecular structures, yielding transferable structural representations without task-specific annotations. Across multiple scoring and docking benchmarks, TopoLIA achieves state-of-the-art performance and consistently outperforms its standard-attention counterpart. Rank analyses show that compact latent dimensions yield the best performance, supporting compact interaction spaces as an effective inductive bias for biomolecular learning. More broadly, LIA provides a general framework for structured, source-target-dependent information exchange that is applicable to diverse scientific and AI problems involving complex heterogeneous interactions.

Molecular 3D structures underpin simulations of thermodynamics, kinetics, crystallization, and nucleation, making their accurate prediction central to drug discovery and materials design. However, molecular geometry can change dramatically across environments. Existing models either ignore environmental effects or train separate models for each environment. We hypothesize that transfer learning across contexts is possible for conformer generation and that a general model will perform better when training data are limited, as in ligand binding and crystallization. We introduce EVA-Flow, a unified framework for environment-aware molecular conformation generation that learns shared chemical structure and adapts it through environment-conditioned generative modeling. Across vacuum, protein-ligand docking, solvation, and crystal packing, pretraining and cross-environment finetuning provide their largest gains in the three data-scarce settings. Evaluation against multiple reference conformations shows that EVA-Flow covers a broad range of solvation conformations. Analyses of molecules shared across environments support its ability to generate different conformations for the same molecule in different environments.

Self-supervised learning has recently gained growing interest in molecular modeling for scientific tasks such as AI-assisted drug discovery. Current studies consider leveraging both 2D and 3D molecular structures for representation learning. However, relying on straightforward alignment strategies that treat each modality separately, these methods fail to exploit the intrinsic correlation between 2D and 3D representations that reflect the underlying structural characteristics of molecules, and only perform coarse-grained molecule-level alignment. To derive fine-grained alignment and promote structural molecule understanding, we introduce an atomic-relation level "blend-then-predict" self-supervised learning approach, MoleBLEND, which first blends atom relations represented by different modalities into one unified relation matrix for joint encoding, then recovers modality-specific information for 2D and 3D structures individually. By treating atom relationships as anchors, MoleBLEND organically aligns and integrates visually dissimilar 2D and 3D modalities of the same molecule at fine-grained atomic level, painting a more comprehensive depiction of each molecule. Extensive experiments show that MoleBLEND achieves state-of-the-art performance across major 2D/3D molecular benchmarks. We further provide theoretical insights from the perspective of mutual-information maximization, demonstrating that our method unifies contrastive, generative (cross-modality prediction) and mask-then-predict (single-modality prediction) objectives into one single cohesive framework.

Hit-like molecular generation with therapeutic potential is essential for target-specific drug discovery. However, the field lacks heterogeneous data and unified frameworks for integrating diverse molecular representations. To bridge this gap, we introduce TextOmics, a pioneering benchmark that establishes one-to-one correspondences between omics expressions and molecular textual descriptions. TextOmics provides a heterogeneous dataset that facilitates molecular generation through representations alignment. Built upon this foundation, we propose ToDi, a generative framework that jointly conditions on omics expressions and molecular textual descriptions to produce biologically relevant, chemically valid, hit-like molecules. ToDi leverages two encoders (OmicsEn and TextEn) to capture multi-level biological and semantic associations, and develops conditional diffusion (DiffGen) for controllable generation. Extensive experiments confirm the effectiveness of TextOmics and demonstrate ToDi outperforms existing state-of-the-art approaches, while also showcasing remarkable potential in zero-shot therapeutic molecular generation. Sources are available at: https://github.com/hala-ToDi.

Molecular property prediction is becoming one of the major applications of graph learning in Web-based services, e.g., online protein structure prediction and drug discovery. A key challenge arises in few-shot scenarios, where only a few labeled molecules are available for predicting unseen properties. Recently, several studies have used in-context learning to capture relationships among molecules and properties, but they face two limitations in: (1) exploiting prior knowledge of functional groups that are causally linked to properties and (2) identifying key substructures directly correlated with properties. We propose CaMol, a context-aware graph causality inference framework, to address these challenges by using a causal inference perspective, assuming that each molecule consists of a latent causal structure that determines a specific property. First, we introduce a context graph that encodes chemical knowledge by linking functional groups, molecules, and properties to guide the discovery of causal substructures. Second, we propose a learnable atom masking strategy to disentangle causal substructures from confounding ones. Third, we introduce a distribution intervener that applies backdoor adjustment by combining causal substructures with chemically grounded confounders, disentangling causal effects from real-world chemical variations. Experiments on diverse molecular datasets showed that CaMol achieved superior accuracy and sample efficiency in few-shot tasks, showing its generalizability to unseen properties. Also, the discovered causal substructures were strongly aligned with chemical knowledge about functional groups, supporting the model interpretability.

Designing molecules that are both property-optimal and readily synthesizable is a central challenge in drug discovery. Existing works that do consider synthesizability can jointly output predicted synthesis routes for generated molecules. However, there has been minimal attention in addressing the ease of synthesis and with flexibility to incorporate desired reaction constraints. On the other hand, virtual screening searches for commercially available compounds, but imposes challenges when scaling to ultra-large (billion-size and beyond) chemical spaces. Here, we propose a generative design framework that unifies synthesis-constrained molecular design and ultra-large-scale virtual screening through steerable and granular synthesizability control. Generated molecules satisfy arbitrary multi-parameter optimization objectives with predicted synthesis routes satisfying mix-and-match constraints: including or avoiding certain reactions, incorporating specific building blocks, and minimizing synthesis route length. In an end-to-end in-house campaign targeting BRD4, we designed molecules synthesizable with specific selected reactions and building blocks, synthesized all six selected compounds, and identified two micromolar binders. We further demonstrate that reaction control enables efficient navigation of ultra-large make-on-demand chemical spaces to identify property-optimal candidates. By applying our framework to Chemspace's Freedom 4.0 make-on-demand space (142 billion molecules), we generated ~320k molecules (0.00023% of the library) on a single consumer-grade GPU (with only 8 GB GPU memory) and identified a micromolar Wee1 binder amongst 60 synthesized candidates. The single unified framework thus enables generating novel synthesizable molecules and retrieving catalogue-ready candidates, offering a flexible solution to mitigating the synthesizability bottleneck.

With the development of computer-assisted techniques, research communities including biochemistry and deep learning have been devoted into the drug discovery field for over a decade. Various applications of deep learning have drawn great attention in drug discovery, such as molecule generation, molecular property prediction, retrosynthesis prediction, and reaction prediction. While most existing surveys only focus on one of the applications, limiting the view of researchers in the community. In this paper, we present a comprehensive review on the aforementioned four aspects, and discuss the relationships among different applications. The latest literature and classical benchmarks are presented for better understanding the development of variety of approaches. We commence by summarizing the molecule representation format in these works, followed by an introduction of recent proposed approaches for each of the four tasks. Furthermore, we review a variety of commonly used datasets and evaluation metrics and compare the performance of deep learning-based models. Finally, we conclude by identifying remaining challenges and discussing the future trend for deep learning methods in drug discovery.

Understanding molecules is key to understanding organisms and driving advances in drug discovery, requiring interdisciplinary knowledge across chemistry and biology. Although large molecular language models have achieved notable success in interpreting molecular structures, their instruction datasets are limited to the specific knowledge from task-oriented datasets and do not fully cover the fundamental characteristics of molecules, hindering their abilities as general-purpose molecular assistants. To address this issue, we propose Mol-LLaMA, a large molecular language model that grasps the general knowledge centered on molecules via multi-modal instruction tuning. To this end, we design key data types that encompass the fundamental features of molecules, incorporating essential knowledge from molecular structures. In addition, to improve understanding of molecular features, we introduce a module that integrates complementary information from different molecular encoders, leveraging the distinct advantages of different molecular representations. Our experimental results demonstrate that Mol-LLaMA is capable of comprehending the general features of molecules and generating relevant responses to users' queries with detailed explanations, implying its potential as a general-purpose assistant for molecular analysis.

Molecular dynamics (MD) simulations play a crucial role in scientific research. Yet their computational cost often limits the timescales and system sizes that can be explored. Most data-driven efforts have been focused on reducing the computational cost of accurate interatomic forces required for solving the equations of motion. Despite their success, however, these machine learning interatomic potentials (MLIPs) are still bound to small time-steps. In this work, we introduce TrajCast, a transferable and data-efficient framework based on autoregressive equivariant message passing networks that directly updates atomic positions and velocities lifting the constraints imposed by traditional numerical integration. We benchmark our framework across various systems, including a small molecule, crystalline material, and bulk liquid, demonstrating excellent agreement with reference MD simulations for structural, dynamical, and energetic properties. Depending on the system, TrajCast allows for forecast intervals up to 30times larger than traditional MD time-steps, generating over 15 ns of trajectory data per day for a solid with more than 4,000 atoms. By enabling efficient large-scale simulations over extended timescales, TrajCast can accelerate materials discovery and explore physical phenomena beyond the reach of traditional simulations and experiments. An open-source implementation of TrajCast is accessible under https://github.com/IBM/trajcast.

Large-scale molecular representation methods have revolutionized applications in material science, such as drug discovery, chemical modeling, and material design. With the rise of transformers, models now learn representations directly from molecular structures. In this study, we develop an encoder-decoder model based on BART that is capable of leaning molecular representations and generate new molecules. Trained on SELFIES, a robust molecular string representation, our model outperforms existing baselines in downstream tasks, demonstrating its potential in efficient and effective molecular data analysis and manipulation.

Diffusion-based samplers learn to sample complex, high-dimensional distributions using energies or log densities alone, without training data. Yet, they remain impractical for molecular sampling because they are often slower than molecular dynamics and miss thermodynamically relevant modes. Inspired by enhanced sampling, we encourage exploration by introducing a sequential bias along bespoke, information-rich, low-dimensional projections of atomic coordinates known as collective variables (CVs). We introduce a repulsive potential centered on the CVs from recent samples, which pushes future samples towards novel CV regions and effectively increases the temperature in the projected space. Our resulting method improves efficiency, mode discovery, enables the estimation of free energy differences, and retains independent sampling from the approximate Boltzmann distribution via reweighting by the bias. On standard peptide conformational sampling benchmarks, the method recovers diverse conformational states and accurate free energy profiles. We are the first to demonstrate reactive sampling using a diffusion-based sampler, capturing bond breaking and formation with universal interatomic potentials at near-first-principles accuracy. The approach resolves reactive energy landscapes at a fraction of the wall-clock time of standard sampling methods, advancing diffusion-based sampling towards practical use in molecular sciences.

Quantitative Structure-Activity Relationship (QSAR) modeling is key in drug discovery, but classical methods face limitations when handling high-dimensional data and capturing complex molecular interactions. This research proposes enhancing QSAR techniques through Quantum Support Vector Machines (QSVMs), which leverage quantum computing principles to process information Hilbert spaces. By using quantum data encoding and quantum kernel functions, we aim to develop more accurate and efficient predictive models.

We investigate a relatively under-explored class of hybrid neurosymbolic models that integrate symbolic learning with neural reasoning to construct data generators meeting formal correctness criteria. In Symbolic Neural Generators (SNGs), symbolic learners examine logical specifications of feasible data from a small set of instances -- sometimes just one. Each specification in turn constrains the conditional information supplied to a neural-based generator, which rejects any instance violating the symbolic specification. Like other neurosymbolic approaches, SNG exploits the complementary strengths of symbolic and neural methods. The outcome of an SNG is a pair (H, X), where H is a symbolic description of feasible instances constructed from data, and X a set of generated new instances that satisfy the description. We introduce a semantics for such systems, based on the construction of appropriate base and fibre partially-ordered sets combined into an overall partial order. We implement an SNG combining a restricted form of Inductive Logic Programming (ILP) with a large language model (LLM) and evaluate it on early-stage drug design. Our main interest is the description and the set of potential inhibitor molecules generated by the SNG. On benchmark problems -- where drug targets are well understood -- SNG performance is statistically comparable to state-of-the-art methods. On exploratory problems with poorly understood targets, generated molecules exhibit binding affinities on par with leading clinical candidates. Experts further find the symbolic specifications useful as preliminary filters, with several generated molecules identified as viable for synthesis and wet-lab testing.

Predicting transcriptomic responses to small-molecule perturbations across cell lines is central to drug discovery, but exhaustive profiling of drug-cell combinations is infeasible. We frame molecular perturbation prediction as retrieve-and-aggregate: approximate an unmeasured drug's response in a cell line by aggregating measured responses of a small set of biologically related compounds. We propose LLM-Guided Retrieval (LGR), where a large language model (LLM) ranks candidate neighbor drugs (restricted to those profiled in the target cell line); after which a fixed mean aggregator combines their observed expression deltas to form the prediction. We evaluate on the Tahoe-100M single-cell perturbation atlas under unseen-drug, unseen-cell-line, and open-world regimes. LGR consistently improves over drug mean, ChemCPA, and chemistry-based kNN baselines, with the strongest gains for unseen cell-line generalization, where it achieves higher correlation and lower error than mean baselines. Across settings, LGR improves directional (sign) accuracy of gene regulation, indicating better recovery of biologically meaningful perturbation effects even when magnitude-based metrics are similar. These results suggest that retrieval quality, rather than predictor complexity, is a key driver of zero-shot molecular perturbation prediction, and that LLMs can provide a useful biological prior when used as constrained retrieval modules.

Drug discovery for neurological disease has traditionally centered on the molecules altered by disease. But the molecules that cause pathology are not necessarily the best points from which to reverse it. Here, we ask which otherwise unaltered molecular control points can be engaged to restore pathological neural circuits toward functional states. We present CircuitATLAS, a provenance-grounded systems-neuroscience knowledge graph and agentic framework for target discovery in circuitopathies. It structures literature-derived relationships across diseases, phenotypes, electrophysiology, circuits, brain regions, cell types and molecular effectors, while deliberately excluding direct disease-gene and disease-protein edges to reduce shortcut reasoning. The graph contains 3.83 million nodes and 7.66 million edges, including 5.31 million LLM-extracted relations, and incorporates structured datasets such as the Human Cell Atlas and new multimodal in vivo measurements. We then introduce an agentic workflow that reasons from measurable disease phenotypes through their circuit and cellular substrates to molecular interventions, therapeutic feasibility and clinical constraints. Finally, we introduce a human-governed in vivo lab-in-the-loop linking hypothesis generation to experimental iteration. Within this framework an agent nominated ATP1A3, the neuronal alpha3 Na+/K+-ATPase, as a control point on cortical excitability; interneuron-restricted expression of ATP1A3 abolished the beta- and gamma-band response to a focal 4-aminopyridine challenge in vivo, and the validated target was then carried into a structure-guided small-molecule campaign terminating in a defined assay to resolve the direction of modulation. CircuitATLAS thus provides a framework for discovering therapeutics based not only on what is molecularly disrupted in disease, but on what can be controlled to restore circuit function.

The efficient exploration of chemical space to design molecules with intended properties enables the accelerated discovery of drugs, materials, and catalysts, and is one of the most important outstanding challenges in chemistry. Encouraged by the recent surge in computer power and artificial intelligence development, many algorithms have been developed to tackle this problem. However, despite the emergence of many new approaches in recent years, comparatively little progress has been made in developing realistic benchmarks that reflect the complexity of molecular design for real-world applications. In this work, we develop a set of practical benchmark tasks relying on physical simulation of molecular systems mimicking real-life molecular design problems for materials, drugs, and chemical reactions. Additionally, we demonstrate the utility and ease of use of our new benchmark set by demonstrating how to compare the performance of several well-established families of algorithms. Surprisingly, we find that model performance can strongly depend on the benchmark domain. We believe that our benchmark suite will help move the field towards more realistic molecular design benchmarks, and move the development of inverse molecular design algorithms closer to designing molecules that solve existing problems in both academia and industry alike.

Recent advances in fast sampling methods for diffusion models have demonstrated significant potential to accelerate generation on image modalities. We apply these methods to 3-dimensional molecular conformations by building on the recently introduced GeoLDM equivariant latent diffusion model (Xu et al., 2023). We evaluate trade-offs between speed gains and quality loss, as measured by molecular conformation structural stability. We introduce Equivariant Latent Progressive Distillation, a fast sampling algorithm that preserves geometric equivariance and accelerates generation from latent diffusion models. Our experiments demonstrate up to 7.5x gains in sampling speed with limited degradation in molecular stability. These results suggest this accelerated sampling method has strong potential for high-throughput in silico molecular conformations screening in computational biochemistry, drug discovery, and life sciences applications.

The development of reliable and extensible molecular mechanics (MM) force fields -- fast, empirical models characterizing the potential energy surface of molecular systems -- is indispensable for biomolecular simulation and computer-aided drug design. Here, we introduce a generalized and extensible machine-learned MM force field, espaloma-0.3, and an end-to-end differentiable framework using graph neural networks to overcome the limitations of traditional rule-based methods. Trained in a single GPU-day to fit a large and diverse quantum chemical dataset of over 1.1M energy and force calculations, espaloma-0.3 reproduces quantum chemical energetic properties of chemical domains highly relevant to drug discovery, including small molecules, peptides, and nucleic acids. Moreover, this force field maintains the quantum chemical energy-minimized geometries of small molecules and preserves the condensed phase properties of peptides, self-consistently parametrizing proteins and ligands to produce stable simulations leading to highly accurate predictions of binding free energies. This methodology demonstrates significant promise as a path forward for systematically building more accurate force fields that are easily extensible to new chemical domains of interest.

While various models and computational tools have been proposed for structure and property analysis of molecules, generating molecules that conform to all desired structures and properties remains a challenge. Here, we introduce a multi-constraint molecular generation large language model, TSMMG, which, akin to a student, incorporates knowledge from various small models and tools, namely, the 'teachers'. To train TSMMG, we construct a large set of text-molecule pairs by extracting molecular knowledge from these 'teachers', enabling it to generate novel molecules that conform to the descriptions through various text prompts. We experimentally show that TSMMG remarkably performs in generating molecules meeting complex, natural language-described property requirements across two-, three-, and four-constraint tasks, with an average molecular validity of over 99% and success ratio of 82.58%, 68.03%, and 67.48%, respectively. The model also exhibits adaptability through zero-shot testing, creating molecules that satisfy combinations of properties that have not been encountered. It can comprehend text inputs with various language styles, extending beyond the confines of outlined prompts, as confirmed through empirical validation. Additionally, the knowledge distillation feature of TSMMG contributes to the continuous enhancement of small models, while the innovative approach to dataset construction effectively addresses the issues of data scarcity and quality, which positions TSMMG as a promising tool in the domains of drug discovery and materials science.

Concerns about hallucinations in Large Language Models (LLMs) have been raised by researchers, yet their potential in areas where creativity is vital, such as drug discovery, merits exploration. In this paper, we come up with the hypothesis that hallucinations can improve LLMs in drug discovery. To verify this hypothesis, we use LLMs to describe the SMILES string of molecules in natural language and then incorporate these descriptions as part of the prompt to address specific tasks in drug discovery. Evaluated on seven LLMs and five classification tasks, our findings confirm the hypothesis: LLMs can achieve better performance with text containing hallucinations. Notably, Llama-3.1-8B achieves an 18.35% gain in ROC-AUC compared to the baseline without hallucination. Furthermore, hallucinations generated by GPT-4o provide the most consistent improvements across models. Additionally, we conduct empirical analyses and a case study to investigate key factors affecting performance and the underlying reasons. Our research sheds light on the potential use of hallucinations for LLMs and offers new perspectives for future research leveraging LLMs in drug discovery.

Recent advances in molecular foundation models have shown impressive performance in molecular property prediction and de novo molecular design, with promising applications in areas such as drug discovery and reaction prediction. Nevertheless, most existing approaches rely exclusively on SMILES representations and overlook both experimental spectra and 3D structural information-two indispensable sources for capturing molecular behavior in real-world scenarios. This limitation reduces their effectiveness in tasks where stereochemistry, spatial conformation, and experimental validation are critical. To overcome these challenges, we propose MolSpectLLM, a molecular foundation model pretrained on Qwen2.5-7B that unifies experimental spectroscopy with molecular 3D structure. By explicitly modeling molecular spectra, MolSpectLLM achieves state-of-the-art performance on spectrum-related tasks, with an average accuracy of 0.53 across NMR, IR, and MS benchmarks. MolSpectLLM also shows strong performance on the spectra analysis task, obtaining 15.5% sequence accuracy and 41.7% token accuracy on Spectra-to-SMILES, substantially outperforming large general-purpose LLMs. More importantly, MolSpectLLM not only achieves strong performance on molecular elucidation tasks, but also generates accurate 3D molecular structures directly from SMILES or spectral inputs, bridging spectral analysis, molecular elucidation, and molecular design. Code are available at https://github.com/Eurekashen/MolSpectLLM{https://github.com/Eurekashen/MolSpectLLM}.

Scientific archives now contain hundreds of petabytes of data across genomics, ecology, climate, and molecular biology that could reveal undiscovered patterns if systematically analyzed at scale. Large-scale, weakly-supervised datasets in language and vision have driven the development of foundation models whose internal representations encode structure (patterns, co-occurrences and statistical regularities) beyond their training objectives. Most existing methods extract structure only for pre-specified targets; they excel at confirmation but do not support open-ended discovery of unknown patterns. We ask whether sparse autoencoders (SAEs) can enable open-ended feature discovery from foundation model representations. We evaluate this question in controlled rediscovery studies, where the learned SAE features are tested for alignment with semantic concepts on a standard segmentation benchmark and compared against strong label-free alternatives on concept-alignment metrics. Applied to ecological imagery, the same procedure surfaces fine-grained anatomical structure without access to segmentation or part labels, providing a scientific case study with ground-truth validation. While our experiments focus on vision with an ecology case study, the method is domain-agnostic and applicable to models in other sciences (e.g., proteins, genomics, weather). Our results indicate that sparse decomposition provides a practical instrument for exploring what scientific foundation models have learned, an important prerequisite for moving from confirmation to genuine discovery.

We present HistoAtlas, a pan-cancer computational atlas that extracts 38 interpretable histomic features from 6,745 diagnostic H&E slides across 21 TCGA cancer types and systematically links every feature to survival, gene expression, somatic mutations, and immune subtypes. All associations are covariate-adjusted, multiple-testing corrected, and classified into evidence-strength tiers. The atlas recovers known biology, from immune infiltration and prognosis to proliferation and kinase signaling, while uncovering compartment-specific immune signals and morphological subtypes with divergent outcomes. Every result is spatially traceable to tissue compartments and individual cells, statistically calibrated, and openly queryable. HistoAtlas enables systematic, large-scale biomarker discovery from routine H&E without specialized staining or sequencing. Data and an interactive web atlas are freely available at https://histoatlas.com .

Constrained synthesizability is an unaddressed challenge in generative molecular design. In particular, designing molecules satisfying multi-parameter optimization objectives, while simultaneously being synthesizable and enforcing the presence of specific commercial building blocks in the synthesis. This is practically important for molecule re-purposing, sustainability, and efficiency. In this work, we propose a novel reward function called TANimoto Group Overlap (TANGO), which uses chemistry principles to transform a sparse reward function into a dense and learnable reward function -- crucial for reinforcement learning. TANGO can augment general-purpose molecular generative models to directly optimize for constrained synthesizability while simultaneously optimizing for other properties relevant to drug discovery using reinforcement learning. Our framework is general and addresses starting-material, intermediate, and divergent synthesis constraints. Contrary to most existing works in the field, we show that incentivizing a general-purpose (without any inductive biases) model is a productive approach to navigating challenging optimization scenarios. We demonstrate this by showing that the trained models explicitly learn a desirable distribution. Our framework is the first generative approach to tackle constrained synthesizability.

Sampling low-energy molecular conformations, spatial arrangements of atoms in a molecule, is a critical task for many different calculations performed in the drug discovery and optimization process. Numerous specialized equivariant networks have been designed to generate molecular conformations from 2D molecular graphs. Recently, non-equivariant transformer models have emerged as a viable alternative due to their capability to scale to improve generalization. However, the concern has been that non-equivariant models require a large model size to compensate the lack of equivariant bias. In this paper, we demonstrate that a well-chosen positional encoding effectively addresses these size limitations. A standard transformer model incorporating relative positional encoding for molecular graphs when scaled to 25 million parameters surpasses the current state-of-the-art non-equivariant base model with 64 million parameters on the GEOM-DRUGS benchmark. We implemented relative positional encoding as a negative attention bias that linearly increases with the shortest path distances between graph nodes at varying slopes for different attention heads, similar to ALiBi, a widely adopted relative positional encoding technique in the NLP domain. This architecture has the potential to serve as a foundation for a novel class of generative models for molecular conformations.

Scaling deep learning models has been at the heart of recent revolutions in language modelling and image generation. Practitioners have observed a strong relationship between model size, dataset size, and performance. However, structure-based architectures such as Graph Neural Networks (GNNs) are yet to show the benefits of scale mainly due to the lower efficiency of sparse operations, large data requirements, and lack of clarity about the effectiveness of various architectures. We address this drawback of GNNs by studying their scaling behavior. Specifically, we analyze message-passing networks, graph Transformers, and hybrid architectures on the largest public collection of 2D molecular graphs. For the first time, we observe that GNNs benefit tremendously from the increasing scale of depth, width, number of molecules, number of labels, and the diversity in the pretraining datasets, resulting in a 30.25% improvement when scaling to 1 billion parameters and 28.98% improvement when increasing size of dataset to eightfold. We further demonstrate strong finetuning scaling behavior on 38 tasks, outclassing previous large models. We hope that our work paves the way for an era where foundational GNNs drive pharmaceutical drug discovery.

How to obtain informative representations of molecules is a crucial prerequisite in AI-driven drug design and discovery. Recent researches abstract molecules as graphs and employ Graph Neural Networks (GNNs) for molecular representation learning. Nevertheless, two issues impede the usage of GNNs in real scenarios: (1) insufficient labeled molecules for supervised training; (2) poor generalization capability to new-synthesized molecules. To address them both, we propose a novel framework, GROVER, which stands for Graph Representation frOm self-superVised mEssage passing tRansformer. With carefully designed self-supervised tasks in node-, edge- and graph-level, GROVER can learn rich structural and semantic information of molecules from enormous unlabelled molecular data. Rather, to encode such complex information, GROVER integrates Message Passing Networks into the Transformer-style architecture to deliver a class of more expressive encoders of molecules. The flexibility of GROVER allows it to be trained efficiently on large-scale molecular dataset without requiring any supervision, thus being immunized to the two issues mentioned above. We pre-train GROVER with 100 million parameters on 10 million unlabelled molecules -- the biggest GNN and the largest training dataset in molecular representation learning. We then leverage the pre-trained GROVER for molecular property prediction followed by task-specific fine-tuning, where we observe a huge improvement (more than 6% on average) from current state-of-the-art methods on 11 challenging benchmarks. The insights we gained are that well-designed self-supervision losses and largely-expressive pre-trained models enjoy the significant potential on performance boosting.

Determining the binding pose of a ligand to a protein, known as molecular docking, is a fundamental task in drug discovery. Generative approaches promise faster, improved, and more diverse pose sampling than physics-based methods, but are often hindered by chemically implausible outputs, poor generalisability, and high computational cost. To address these challenges, we introduce a novel fragmentation scheme, leveraging inductive biases from structural chemistry, to decompose ligands into rigid-body fragments. Building on this decomposition, we present SigmaDock, an SE(3) Riemannian diffusion model that generates poses by learning to reassemble these rigid bodies within the binding pocket. By operating at the level of fragments in SE(3), SigmaDock exploits well-established geometric priors while avoiding overly complex diffusion processes and unstable training dynamics. Experimentally, we show SigmaDock achieves state-of-the-art performance, reaching Top-1 success rates (RMSD<2 & PB-valid) above 79.9% on the PoseBusters set, compared to 12.7-30.8% reported by recent deep learning approaches, whilst demonstrating consistent generalisation to unseen proteins. SigmaDock is the first deep learning approach to surpass classical physics-based docking under the PB train-test split, marking a significant leap forward in the reliability and feasibility of deep learning for molecular modelling.

Matched molecular pairs (MMPs) capture the local chemical edits that medicinal chemists routinely use to design analogs, but existing ML approaches either operate at the whole-molecule level with limited edit controllability or learn MMP-style edits from restricted settings and small models. We propose a variable-to-variable formulation of analog generation and train a foundation model on large-scale MMP transformations (MMPTs) to generate diverse variables conditioned on an input variable. To enable practical control, we develop prompting mechanisms that let the users specify preferred transformation patterns during generation. We further introduce MMPT-RAG, a retrieval-augmented framework that uses external reference analogs as contextual guidance to steer generation and generalize from project-specific series. Experiments on general chemical corpora and patent-specific datasets demonstrate improved diversity, novelty, and controllability, and show that our method recovers realistic analog structures in practical discovery scenarios.

Conventional tissue image analysis software provides foundational capabilities for cellular analysis, including segmentation, basic morphological feature extraction, and spatial organization analysis. However, these tools often require manual intervention and are not well integrated with code-driven automation, limiting efficiency and scalability for complex spatial tissue studies. In addition, they offer limited flexibility for custom analyses, as they typically support only a fixed set of pre-implemented spatial cellular features. To address these limitations, we propose CodeCytos, a coding-based reasoning agent framework that enables dynamic, programmable interaction with spatial molecular imaging data to improve automation and customization. CodeCytos is designed to streamline the exploration of custom spatial cellular features and adapt to diverse research needs. We demonstrate its utility through case studies on four expert-curated datasets from distinct tissue types: frontal cortex, non-small-cell lung cancer, pancreas, and tonsil. We evaluate CodeCytos under a realistic minimal prompt setting, where bioscientists pose simple questions without task-specific instructions or contextual information about spatial cellular analysis, and benchmark multiple LLM backbones with strong coding capabilities. We further show that incorporating tailored, domain-agnostic few-shot in-context coding-reasoning examples (randomly sampled demonstrations outside the spatial analysis domain) can substantially improve performance without requiring costly, expert-crafted in-domain demonstrations. Overall, CodeCytos outperforms baseline approaches, highlighting the potential of code-action agents to assist with custom feature exploration in spatial molecular imaging and to accelerate biomarker discovery.

Large language models (LLMs) are widely applied across chemical tasks, such as molecular property prediction, which underpins drug discovery. Molecular LLMs represent a molecule through several modalities, notably a 1D SMILES sequence or a 2D molecular graph. Both encode molecular information implicitly, so the contribution of individual substructures remains opaque. Retrieval and augmentation methods add context, but from external sources. However, the cues chemists reason over are the internal substructures that drive a property up or down. We propose MR-MoL, a multi-granular rationale-guided molecular LLM that supplies this evidence directly. A fine-tuned GNN scores each substructure through masking, and the most influential ones are serialized as a ranked, direction-tagged rationale that the LLM reads alongside the SMILES sequence and molecular graph. The rationale spans three levels of granularity: Murcko scaffolds with their side chains, BRICS fragments, and functional groups. This is, to our knowledge, the first method to expose GNN-derived attributions to an LLM as evidence for property prediction. On eight MoleculeNet tasks, MR-MoL achieves the best overall results among generalist models and narrows the gap to specialist models tuned for each task. Five diagnostics further confirm that the model reads the rationale rather than merely benefiting from its presence. Its direction, rank, and substructure each shape the prediction, and its attributions reproduce known structure-property relationships.

Models based on machine learning can enable accurate and fast molecular property predictions, which is of interest in drug discovery and material design. Various supervised machine learning models have demonstrated promising performance, but the vast chemical space and the limited availability of property labels make supervised learning challenging. Recently, unsupervised transformer-based language models pretrained on a large unlabelled corpus have produced state-of-the-art results in many downstream natural language processing tasks. Inspired by this development, we present molecular embeddings obtained by training an efficient transformer encoder model, MoLFormer, which uses rotary positional embeddings. This model employs a linear attention mechanism, coupled with highly distributed training, on SMILES sequences of 1.1 billion unlabelled molecules from the PubChem and ZINC datasets. We show that the learned molecular representation outperforms existing baselines, including supervised and self-supervised graph neural networks and language models, on several downstream tasks from ten benchmark datasets. They perform competitively on two others. Further analyses, specifically through the lens of attention, demonstrate that MoLFormer trained on chemical SMILES indeed learns the spatial relationships between atoms within a molecule. These results provide encouraging evidence that large-scale molecular language models can capture sufficient chemical and structural information to predict various distinct molecular properties, including quantum-chemical properties.

In recent years, groundbreaking advancements in natural language processing have culminated in the emergence of powerful large language models (LLMs), which have showcased remarkable capabilities across a vast array of domains, including the understanding, generation, and translation of natural language, and even tasks that extend beyond language processing. In this report, we delve into the performance of LLMs within the context of scientific discovery, focusing on GPT-4, the state-of-the-art language model. Our investigation spans a diverse range of scientific areas encompassing drug discovery, biology, computational chemistry (density functional theory (DFT) and molecular dynamics (MD)), materials design, and partial differential equations (PDE). Evaluating GPT-4 on scientific tasks is crucial for uncovering its potential across various research domains, validating its domain-specific expertise, accelerating scientific progress, optimizing resource allocation, guiding future model development, and fostering interdisciplinary research. Our exploration methodology primarily consists of expert-driven case assessments, which offer qualitative insights into the model's comprehension of intricate scientific concepts and relationships, and occasionally benchmark testing, which quantitatively evaluates the model's capacity to solve well-defined domain-specific problems. Our preliminary exploration indicates that GPT-4 exhibits promising potential for a variety of scientific applications, demonstrating its aptitude for handling complex problem-solving and knowledge integration tasks. Broadly speaking, we evaluate GPT-4's knowledge base, scientific understanding, scientific numerical calculation abilities, and various scientific prediction capabilities.

Molecule discovery serves as a cornerstone in numerous scientific domains, fueling the development of new materials and innovative drug designs. Recent developments of in-silico molecule discovery have highlighted the promising results of cross-modal techniques, which bridge molecular structures with their descriptive annotations. However, these cross-modal methods frequently encounter the issue of data scarcity, hampering their performance and application. In this paper, we address the low-resource challenge by utilizing artificially-real data generated by Large Language Models (LLMs). We first introduce a retrieval-based prompting strategy to construct high-quality pseudo data, then explore the optimal method to effectively leverage this pseudo data. Experiments show that using pseudo data for domain adaptation outperforms all existing methods, while also requiring a smaller model scale, reduced data size and lower training cost, highlighting its efficiency. Furthermore, our method shows a sustained improvement as the volume of pseudo data increases, revealing the great potential of pseudo data in advancing low-resource cross-modal molecule discovery.

Large language models (LLMs), especially Explicit Long Chain-of-Thought (CoT) reasoning models like DeepSeek-R1 and QWQ, have demonstrated powerful reasoning capabilities, achieving impressive performance in commonsense reasoning and mathematical inference. Despite their effectiveness, Long-CoT reasoning models are often criticized for their limited ability and low efficiency in knowledge-intensive domains such as molecule discovery. Success in this field requires a precise understanding of domain knowledge, including molecular structures and chemical principles, which is challenging due to the inherent complexity of molecular data and the scarcity of high-quality expert annotations. To bridge this gap, we introduce Mol-R1, a novel framework designed to improve explainability and reasoning performance of R1-like Explicit Long-CoT reasoning LLMs in text-based molecule generation. Our approach begins with a high-quality reasoning dataset curated through Prior Regulation via In-context Distillation (PRID), a dedicated distillation strategy to effectively generate paired reasoning traces guided by prior regulations. Building upon this, we introduce MoIA, Molecular Iterative Adaptation, a sophisticated training strategy that iteratively combines Supervised Fine-tuning (SFT) with Reinforced Policy Optimization (RPO), tailored to boost the reasoning performance of R1-like reasoning models for molecule discovery. Finally, we examine the performance of Mol-R1 in the text-based molecule reasoning generation task, showing superior performance against existing baselines.

Large language models (LLMs) have gained significant attention in chemistry. However, most existing datasets center on molecular-level property prediction and overlook the role of fine-grained functional group (FG) information. Incorporating FG-level data can provide valuable prior knowledge that links molecular structures with textual descriptions, which can be used to build more interpretable, structure-aware LLMs for reasoning on molecule-related tasks. Moreover, LLMs can learn from such fine-grained information to uncover hidden relationships between specific functional groups and molecular properties, thereby advancing molecular design and drug discovery. Here, we introduce FGBench, a dataset comprising 625K molecular property reasoning problems with functional group information. Functional groups are precisely annotated and localized within the molecule, which ensures the dataset's interoperability thereby facilitating further multimodal applications. FGBench includes both regression and classification tasks on 245 different functional groups across three categories for molecular property reasoning: (1) single functional group impacts, (2) multiple functional group interactions, and (3) direct molecular comparisons. In the benchmark of state-of-the-art LLMs on 7K curated data, the results indicate that current LLMs struggle with FG-level property reasoning, highlighting the need to enhance reasoning capabilities in LLMs for chemistry tasks. We anticipate that the methodology employed in FGBench to construct datasets with functional group-level information will serve as a foundational framework for generating new question-answer pairs, enabling LLMs to better understand fine-grained molecular structure-property relationships. The dataset and evaluation code are available at https://github.com/xuanliugit/FGBench.