Spaces:
Running
Running
| """ADMET descriptor computation using RDKit — industrial-grade panel. | |
| Computes 50+ molecular descriptors including: | |
| - Core physicochemical properties (MW, LogP, TPSA, HBD, HBA, etc.) | |
| - Extended topological descriptors (Fsp3, aromatic rings, MR, volume, complexity) | |
| - Drug-likeness filters (Lipinski, Veber, Ghose, Egan, MDDR, PAINS, Brenk) | |
| - ADMET predictions (absorption, distribution, metabolism, toxicity, clearance) | |
| - Structural alerts and functional group analysis | |
| """ | |
| from __future__ import annotations | |
| import logging | |
| import os | |
| logger = logging.getLogger(__name__) | |
| def _fg(mol, name: str) -> int: | |
| """Safely call a Fragments.fr_* function, returning 0 if unavailable.""" | |
| from rdkit.Chem import Fragments | |
| fn = getattr(Fragments, name, None) | |
| if fn is None: | |
| return 0 | |
| try: | |
| return fn(mol) | |
| except Exception: | |
| return 0 | |
| # --- BOILED-Egg (Daina & Zoete, ChemMedChem 2016) ------------------------- | |
| # Boundary polygons (x=TPSA Ų, y=WLOGP) from the paper's supporting info — | |
| # identical to the shapes SwissADME uses for the GI-absorption and BBB | |
| # classification and its graphical output. | |
| _GIA_COORDS = ( | |
| (97.80552243681136, -2.227039047489081), (101.88198219217963, -2.1900004937640487), | |
| (105.83667285876659, -2.1352635055090943), (109.65398707923741, -2.063044104609906), | |
| (113.31885965832892, -1.9736273080479292), (116.81682701829244, -1.8673660030685453), | |
| (120.13408428002757, -1.7446795544963347), (123.25753974463277, -1.6060521496937052), | |
| (126.17486656036041, -1.452030887694577), (128.87455137106866, -1.2832236200544374), | |
| (131.3459397541782, -1.100296551937959), (133.57927826881107, -0.903971612911568), | |
| (135.56575294816514, -0.6950236078172709), (137.29752408421504, -0.4742771589719089), | |
| (138.76775716745777, -0.2426034517596168), (139.97064985959926, -0.0009167964611120461), | |
| (140.90145489273314, 0.2498289801112721), (141.556498804638, 0.5086442989322527), | |
| (141.9331964362546, 0.7745077341799151), (142.03006113412775, 1.0463700443367885), | |
| (141.84671061754818, 1.323158313066756), (141.38386848723997, 1.6037801835256746), | |
| (140.64336136963902, 1.88712816939478), (139.628111708033, 2.1720840256232266), | |
| (138.34212622901268, 2.457523161630431), (136.790480129753, 2.7423190795513075), | |
| (134.97929704852805, 3.025347820008701), (132.91572489750854, 3.3054923978675586), | |
| (130.60790765321815, 3.5816472104649564), (128.06495321597865, 3.8527224009187018), | |
| (125.29689746518848, 4.1176481592945535), (122.31466465229157, 4.375378944657261), | |
| (119.13002428774791, 4.624897611343), (115.75554469215258, 4.865219423168597), | |
| (112.20454339481628, 5.095395939735363), (108.49103457556141, 5.314518759490062), | |
| (104.62967375715677, 5.521723104770812), (100.63569996666462, 5.716191234689457), | |
| (96.52487559396305, 5.8971556723812375), (92.313424184794, 6.063902233885377), | |
| (88.0179664138405, 6.215772846702879), (83.6554544905163, 6.352168146908026), | |
| (79.2431052563408, 6.472549844564003), (74.79833223793057, 6.576442848107324), | |
| (70.3386769237657, 6.663437139317204), (65.88173953594848, 6.733189391470147), | |
| (61.445109570167645, 6.785424324293678), (57.04629637799464, 6.8199357903718125), | |
| (52.7026600654724, 6.836587588714733), (48.43134298070782, 6.83531400228186), | |
| (44.24920206085525, 6.816120057336999), (40.17274230548697, 6.779081503611968), | |
| (36.218051638900036, 6.7243445153570125), (32.400737418429216, 6.652125114457824), | |
| (28.735864839337697, 6.562708317895847), (25.237897479374148, 6.456447012916463), | |
| (21.92064021763908, 6.333760564344252), (18.79718475303387, 6.195133159541625), | |
| (15.879857937306236, 6.0411118975424944), (13.180173126598005, 5.872304629902357), | |
| (10.708784743488392, 5.689377561785878), (8.475446228855569, 5.493052622759485), | |
| (6.488971549501496, 5.284104617665191), (4.757200413451594, 5.063358168819828), | |
| (3.286967330208895, 4.8316844616075345), (2.084074638067364, 4.589997806309031), | |
| (1.1532696049334672, 4.339252029736645), (0.4982256930286379, 4.0804367109156665), | |
| (0.12152806141202838, 3.8145732756680006), (0.024663363538902687, 3.5427109655111297), | |
| (0.2080138801184492, 3.265922696781163), (0.6708560104266521, 2.9853008263222423), | |
| (1.4113631280275918, 2.701952840453139), (2.426612789633675, 2.416996984224689), | |
| (3.7125982686539536, 2.1315578482174877), (5.264244367913619, 1.846761930296613), | |
| (7.0754274491385845, 1.5637331898392164), (9.138999600158078, 1.2835886119803601), | |
| (11.4468168444485, 1.0074337993829612), (13.989771281687991, 0.7363586089292161), | |
| (16.75782703247815, 0.4714328505533679), (19.740059845375065, 0.21370206519065607), | |
| (22.92470020991869, -0.03581660149508132), (26.29917980551407, -0.27613841332067823), | |
| (29.85018110285037, -0.506314929887444), (33.563689922105276, -0.7254377496421445), | |
| (37.425050740509896, -0.9326420949228948), (41.419024531002, -1.127110224841536), | |
| (45.529848903703616, -1.3080746625333208), (49.7413003128726, -1.4748212240374596), | |
| (54.0367580838262, -1.6266918368549592), (58.39927000715034, -1.7630871370601089), | |
| (62.81161924132584, -1.8834688347160848), (67.25639225973609, -1.9873618382594065), | |
| (71.71604757390092, -2.074356129469285), (76.17298496171819, -2.144108381622228), | |
| (80.609614927499, -2.196343314445759), (85.00842811967199, -2.2308547805238947), | |
| (89.35206443219425, -2.247506578866816), (93.62338151695882, -2.2462329924339417), | |
| (97.80552243681143, -2.2270390474890807), | |
| ) | |
| _BBB_COORDS = ( | |
| (40.97017925131679, 0.4062562899766126), (43.53440363567211, 0.4169942065264866), | |
| (46.077057183913354, 0.4386559712786629), (48.58810520411346, 0.4711560951439837), | |
| (51.05763773692548, 0.5143663149814472), (53.47590866566447, 0.5681160997942261), | |
| (55.83337417977759, 0.6321933237376053), (58.120730439904186, 0.7063451032827793), | |
| (60.328950295879224, 0.7902787952326094), (62.449318912770856, 0.8836631516506256), | |
| (64.47346816435247, 0.9861296271452998), (66.39340965827392, 1.0972738333503356), | |
| (68.20156626259653, 1.2166571348607977), (69.8908020092712, 1.3438083803266692), | |
| (71.45445025654422, 1.4782257618719723), (72.88633999914657, 1.61937879550121), | |
| (74.1808202224323, 1.766710414677333), (75.33278220435197, 1.9196391688088683), | |
| (76.33767967724427, 2.07756151796976), (77.19154676987765, 2.239854214795729), | |
| (77.89101365893231, 2.405876764156885), (78.43331986815312, 2.5749739508993854), | |
| (78.81632516268847, 2.7464784256803143), (79.03851799561927, 2.9197133386906526), | |
| (79.09902147334422, 3.093995010872254), (78.99759681627812, 3.2686356320867374), | |
| (78.73464430120595, 3.442945975587881), (78.31120168157305, 3.6162381180847065), | |
| (77.72894009194661, 3.7878281546604287), (76.99015745281086, 3.9570388978327133), | |
| (76.09776940172482, 4.1232025501032945), (75.05529778663279, 4.285663339449613), | |
| (73.86685676673952, 4.4437801073573935), (72.53713657580352, 4.596928839180382), | |
| (71.071385011927, 4.744505126841076), (69.47538672689447, 4.885926554153269), | |
| (67.75544039679461, 5.020634995352665), (65.91833386402362, 5.148098817764284), | |
| (63.97131734877222, 5.267814979913747), (61.92207483571886, 5.3793110168021645), | |
| (59.77869374885272, 5.482146904509627), (57.549633034105966, 5.575916796768607), | |
| (55.243689775758746, 5.660250626653745), (52.86996447836648, 5.734815567066945), | |
| (50.43782515122604, 5.799317344253877), (47.956870337122915, 5.853501399168046), | |
| (45.43689123126793, 5.897153892099043), (42.8878330399229, 5.930102546600198), | |
| (40.319755731215174, 5.952217329385), (37.74279433303931, 5.9634109635090855), | |
| (35.167118934732244, 5.963639272812449), (32.602894550376924, 5.952901356262576), | |
| (30.06024100213569, 5.931239591510399), (27.54919298193556, 5.898739467645077), | |
| (25.079660449123548, 5.855529247807613), (22.66138952038456, 5.801779462994835), | |
| (20.303924006271433, 5.7377022390514565), (18.016567746144844, 5.663550459506283), | |
| (15.808347890169804, 5.579616767556452), (13.687979273278186, 5.486232411138436), | |
| (11.663830021696565, 5.38376593564376), (9.743888527775118, 5.272621729438726), | |
| (7.935731923452518, 5.153238427928264), (6.2464961767778435, 5.026087182462394), | |
| (4.682847929504812, 4.8916698009170885), (3.2509581869024937, 4.750516767287851), | |
| (1.9564779636167104, 4.603185148111728), (0.8045159816970635, 4.450256393980193), | |
| (-0.20038149119524168, 4.2923340448193015), (-1.054248583828624, 4.130041347993332), | |
| (-1.7537154728832645, 3.9640187986321784), (-2.2960216821040977, 3.7949216118896762), | |
| (-2.67902697663943, 3.623417137108748), (-2.9012198095702453, 3.450182224098408), | |
| (-2.961723287295181, 3.275900551916808), (-2.8602986302290945, 3.1012599307023248), | |
| (-2.5973461151568977, 2.9269495872011797), (-2.173903495524005, 2.753657444704355), | |
| (-1.5916419058975677, 2.582067408128632), (-0.8528592667618298, 2.4128566649563483), | |
| (0.039528784324221584, 2.246693012685768), (1.0820003994162777, 2.0842322233394484), | |
| (2.2704414193095257, 1.9261154554316693), (3.6001616102455305, 1.7729667236086788), | |
| (5.0659131741220245, 1.6253904359479865), (6.6619114591545925, 1.4839690086357915), | |
| (8.381857789254436, 1.3492605674363958), (10.21896432202541, 1.2217967450247778), | |
| (12.165980837276834, 1.102080582875313), (14.215223350330179, 0.9905845459868972), | |
| (16.358604437196348, 0.8877486582794322), (18.58766515194309, 0.7939787660204534), | |
| (20.893608410290287, 0.7096449361353171), (23.26733370768257, 0.6350799957221163), | |
| (25.699473034822983, 0.5705782185351836), (28.18042784892613, 0.5163941636210154), | |
| (30.700406954781126, 0.4727416706900189), (33.24946514612614, 0.4397930161888647), | |
| (35.817542454833884, 0.41767823340406107), (38.39450385300971, 0.4064845992799761), | |
| (40.970179251316814, 0.4062562899766126), | |
| ) | |
| def _point_in_polygon(px: float, py: float, poly) -> bool: | |
| """Ray-casting point-in-polygon test (points are (x=TPSA, y=WLOGP)).""" | |
| inside = False | |
| j = len(poly) - 1 | |
| for i in range(len(poly)): | |
| xi, yi = poly[i] | |
| xj, yj = poly[j] | |
| if (yi > py) != (yj > py): | |
| x_cross = xi + (py - yi) / (yj - yi + 1e-12) * (xj - xi) | |
| if px < x_cross: | |
| inside = not inside | |
| j = i | |
| return inside | |
| def _esol_log_s(mol, wlogp: float) -> float: | |
| """Delaney ESOL aqueous solubility (SwissADME substitutes XLOGP3 for | |
| Daylight CLOGP; we use WLOGP, which is within ~0.1 log unit for most | |
| drug-like molecules).""" | |
| from rdkit import Chem | |
| from rdkit.Chem import Descriptors | |
| heavy = mol.GetNumHeavyAtoms() | |
| aromatic_heavy = sum(1 for a in mol.GetAtoms() | |
| if a.GetIsAromatic() and a.GetAtomicNum() > 1) | |
| ap = aromatic_heavy / heavy if heavy else 0.0 | |
| rb = Descriptors.rdMolDescriptors.CalcNumRotatableBonds(mol) | |
| mw = Descriptors.MolWt(mol) | |
| return 0.16 - 0.63 * wlogp - 0.0062 * mw + 0.066 * rb - 0.74 * ap | |
| def _solubility_class(log_s: float) -> str: | |
| if log_s > 0: | |
| return "Highly soluble" | |
| if log_s > -2: | |
| return "Soluble" | |
| if log_s > -4: | |
| return "Moderately soluble" | |
| if log_s > -6: | |
| return "Slightly soluble" | |
| if log_s > -8: | |
| return "Very slightly soluble" | |
| return "Insoluble" | |
| def _martin_bioavailability(mol, tpsa: float, lipinski_pass: bool) -> float: | |
| """Abbott/Martin Bioavailability Score (Martin, J. Med. Chem. 2005). | |
| Acidic (net negative) compounds are scored by TPSA; neutral/zwitterionic/ | |
| cationic compounds by rule-of-five compliance.""" | |
| if sum(a.GetFormalCharge() for a in mol.GetAtoms()) < 0: | |
| if tpsa <= 75: | |
| return 0.85 | |
| if tpsa < 150: | |
| return 0.56 | |
| return 0.11 | |
| return 0.55 if lipinski_pass else 0.17 | |
| def compute_descriptors(smiles: str) -> dict: | |
| """Compute comprehensive ADMET descriptors from a SMILES string.""" | |
| from rdkit import Chem | |
| from rdkit.Chem import ( | |
| Descriptors, Lipinski, QED, rdMolDescriptors, | |
| EState, Fragments, Crippen, | |
| ) | |
| from rdkit.Chem.MolSurf import LabuteASA | |
| mol = Chem.MolFromSmiles(smiles) | |
| if mol is None: | |
| raise ValueError(f"Invalid SMILES: {smiles!r}") | |
| n_heavy = mol.GetNumHeavyAtoms() | |
| n_rings = mol.GetRingInfo().NumRings() | |
| n_aromatic_rings = sum(1 for ring in mol.GetRingInfo().AtomRings() | |
| if all(mol.GetAtomWithIdx(a).GetIsAromatic() for a in ring)) | |
| # ---- Core physicochemical properties ---- | |
| mw = round(Descriptors.MolWt(mol), 2) | |
| logp = round(Descriptors.MolLogP(mol), 2) | |
| # SwissADME TPSA uses the Ertl fragmental method including S and P. | |
| tpsa = round(Descriptors.TPSA(mol, includeSandP=True), 2) | |
| hbd = Lipinski.NumHDonors(mol) | |
| # SwissADME "H-bond acceptors" = all N + O atoms (OpenBabel count). | |
| # CalcNumLipinskiHBA is a pure N+O count; the plain NumHAcceptors / | |
| # CalcNumHBA exclude e.g. ester carbonyl oxygens and would show 3 for | |
| # aspirin instead of SwissADME's 4. | |
| hba = rdMolDescriptors.CalcNumLipinskiHBA(mol) | |
| rotatable = Lipinski.NumRotatableBonds(mol) | |
| heavy_atoms = n_heavy | |
| formula = rdMolDescriptors.CalcMolFormula(mol) | |
| qed_score = round(QED.qed(mol), 4) | |
| # ---- Extended topological descriptors ---- | |
| fsp3 = round(Descriptors.FractionCSP3(mol), 4) | |
| mr = round(Crippen.MolMR(mol), 2) # molar refractivity | |
| mol_volume = 0.0 | |
| try: | |
| mol_volume = round(rdMolDescriptors.CalcMolecularVolume(mol), 2) | |
| except AttributeError: | |
| try: | |
| from rdkit.Chem import Descriptors3D | |
| mol_volume = round(Descriptors3D.CalcVolume(mol), 2) | |
| except Exception: | |
| mol_volume = 0.0 | |
| except Exception: | |
| mol_volume = 0.0 | |
| complexity = 0.0 | |
| if os.name != "nt": | |
| try: | |
| complexity = round(Descriptors.BalabanJ(mol), 4) | |
| except Exception: | |
| pass | |
| try: | |
| wiener = Descriptors.WeinerIndex(mol) | |
| except Exception: | |
| wiener = 0 | |
| try: | |
| zagreb = Descriptors.ZagrebIndex(mol) | |
| except Exception: | |
| zagreb = 0 | |
| num_heteroatoms = Lipinski.NumHeteroatoms(mol) | |
| num_amide_bonds = rdMolDescriptors.CalcNumAmideBonds(mol) | |
| num_atom_stereocenters = rdMolDescriptors.CalcNumAtomStereoCenters(mol) | |
| num_unspecified_stereocenters = rdMolDescriptors.CalcNumUnspecifiedAtomStereoCenters(mol) | |
| labute_asa = round(LabuteASA(mol), 2) | |
| estate_sum = round(sum(EState.EStateIndices(mol)), 2) | |
| # Ring descriptors | |
| ring_count = n_rings | |
| aromatic_ring_count = n_aromatic_rings | |
| aliphatic_ring_count = ring_count - aromatic_ring_count | |
| num_saturated_rings = sum(1 for ring in mol.GetRingInfo().AtomRings() | |
| if all(not mol.GetAtomWithIdx(a).GetIsAromatic() and | |
| mol.GetAtomWithIdx(a).GetDegree() == 3 | |
| for a in ring)) | |
| # Functional group counts (safe — tolerates missing rdkit attributes) | |
| num_oh = _fg(mol, "fr_Al_OH") + _fg(mol, "fr_Ar_OH") | |
| num_nh = _fg(mol, "fr_NH0") + _fg(mol, "fr_NH1") + _fg(mol, "fr_NH2") | |
| num_aliphatic_oh = _fg(mol, "fr_Al_OH") | |
| num_aromatic_oh = _fg(mol, "fr_Ar_OH") | |
| num_carboxylic = _fg(mol, "fr_COO") | |
| num_ester = _fg(mol, "fr_ester") | |
| num_ether = _fg(mol, "fr_ether") | |
| num_ketone = _fg(mol, "fr_ketone") | |
| num_aldehyde = _fg(mol, "fr_aldehyde") | |
| num_halogen = _fg(mol, "fr_halogen") | |
| num_sulfonamide = _fg(mol, "fr_sulfonamide") | |
| num_nitro = _fg(mol, "fr_nitro") | |
| num_phenol = _fg(mol, "fr_phenol") | |
| num_amine = _fg(mol, "fr_NH0") + _fg(mol, "fr_NH1") | |
| # ---- Lipinski Rule of Five ---- | |
| lip_violations = [] | |
| if mw > 500: | |
| lip_violations.append(f"MW {mw} > 500") | |
| if logp > 5: | |
| lip_violations.append(f"LogP {logp} > 5") | |
| if hbd > 5: | |
| lip_violations.append(f"HBD {hbd} > 5") | |
| if hba > 10: | |
| lip_violations.append(f"HBA {hba} > 10") | |
| lipinski = {"pass": len(lip_violations) <= 1, "violations": lip_violations, "violation_count": len(lip_violations)} | |
| # ---- Veber rules ---- | |
| veber_violations = [] | |
| if rotatable > 10: | |
| veber_violations.append(f"Rotatable bonds {rotatable} > 10") | |
| if tpsa > 140: | |
| veber_violations.append(f"TPSA {tpsa} > 140") | |
| veber = {"pass": len(veber_violations) == 0, "violations": veber_violations, "violation_count": len(veber_violations)} | |
| # ---- Ghose filter (160 <= MW <= 480, -0.4 <= LogP <= 5.6, 20 <= atoms <= 70) ---- | |
| ghose_violations = [] | |
| if mw < 160 or mw > 480: | |
| ghose_violations.append(f"MW {mw} outside 160-480") | |
| if logp < -0.4 or logp > 5.6: | |
| ghose_violations.append(f"LogP {logp} outside -0.4-5.6") | |
| if n_heavy < 20 or n_heavy > 70: | |
| ghose_violations.append(f"Heavy atoms {n_heavy} outside 20-70") | |
| if mr < 40 or mr > 130: | |
| ghose_violations.append(f"MR {mr} outside 40-130") | |
| ghose = {"pass": len(ghose_violations) == 0, "violations": ghose_violations, "violation_count": len(ghose_violations)} | |
| # ---- Egan filter (oral absorption: TPSA <= 132, LogP <= 5.88) ---- | |
| egan_violations = [] | |
| if tpsa > 132: | |
| egan_violations.append(f"TPSA {tpsa} > 132 (poor absorption)") | |
| if logp > 5.88: | |
| egan_violations.append(f"LogP {logp} > 5.88 (poor absorption)") | |
| egan = {"pass": len(egan_violations) == 0, "violations": egan_violations, "violation_count": len(egan_violations)} | |
| # ---- Muegge filter (Bayer) — SwissADME drug-likeness panel ---- | |
| muegge_violations = [] | |
| if mw < 200 or mw > 600: | |
| muegge_violations.append(f"MW {mw} outside 200-600") | |
| if logp < -2 or logp > 5: | |
| muegge_violations.append(f"LogP {logp} outside -2-5") | |
| if tpsa > 150: | |
| muegge_violations.append(f"TPSA {tpsa} > 150") | |
| if ring_count > 7: | |
| muegge_violations.append(f"Ring count {ring_count} > 7") | |
| if n_heavy <= 4: | |
| muegge_violations.append(f"Carbons {n_heavy} <= 4") | |
| if num_heteroatoms <= 1: | |
| muegge_violations.append(f"Heteroatoms {num_heteroatoms} <= 1") | |
| if rotatable > 15: | |
| muegge_violations.append(f"Rotatable bonds {rotatable} > 15") | |
| if hbd > 5: | |
| muegge_violations.append(f"HBD {hbd} > 5") | |
| if hba > 10: | |
| muegge_violations.append(f"HBA {hba} > 10") | |
| muegge = {"pass": len(muegge_violations) == 0, "violations": muegge_violations, "violation_count": len(muegge_violations)} | |
| # ---- MDDR-like rules (drug-like space) ---- | |
| mddr_violations = [] | |
| if mw < 200 or mw > 700: | |
| mddr_violations.append(f"MW {mw} outside 200-700") | |
| if logp < -2 or logp > 6: | |
| mddr_violations.append(f"LogP {logp} outside -2-6") | |
| if tpsa > 180: | |
| mddr_violations.append(f"TPSA {tpsa} > 180") | |
| if rotatable > 15: | |
| mddr_violations.append(f"Rotatable bonds {rotatable} > 15") | |
| if ring_count > 8: | |
| mddr_violations.append(f"Ring count {ring_count} > 8") | |
| mddr = {"pass": len(mddr_violations) == 0, "violations": mddr_violations, "violation_count": len(mddr_violations)} | |
| # ---- PAINS alerts (Pan Assay Interference Compounds) ---- | |
| pains_patterns = [ | |
| ("Rhodanine", r"[N,n,O,o,S,s]C(=O)CSC(=S)"), | |
| ("PAINS_1", r"C=CC(=O)"), # acrylamide | |
| ("Quinone", r"C1=CC(=O)C=CC1=O"), | |
| ("Michael_acceptor", r"C=CC(=O)[N,O]"), | |
| ("Catechol", r"C1=CC=C(O)C(O)=C1"), | |
| ("Hydroquinone", r"C1=CC=C(O)C=C1O"), | |
| ("Aniline", r"Nc1ccccc1"), | |
| ("Azobenzene", r"N=Nc1ccccc1"), | |
| ] | |
| pains_hits = [] | |
| for name, smarts in pains_patterns: | |
| pattern = Chem.MolFromSmarts(smarts) | |
| if pattern and mol.HasSubstructMatch(pattern): | |
| pains_hits.append(name) | |
| pains = {"pass": len(pains_hits) == 0, "alerts": pains_hits, "alert_count": len(pains_hits)} | |
| # ---- Brenk structural alerts ---- | |
| brenk_alerts = [] | |
| if _fg(mol, "fr_halogen") > 2: | |
| brenk_alerts.append("Multiple halogen substituents") | |
| if _fg(mol, "fr_nitro") > 0: | |
| brenk_alerts.append("Nitro group (mutagenicity concern)") | |
| if _fg(mol, "fr_sulfonamide") > 0: | |
| brenk_alerts.append("Sulfonamide (hypersensitivity risk)") | |
| if n_aromatic_rings > 5: | |
| brenk_alerts.append(f"Many aromatic rings ({n_aromatic_rings}) — metabolic liability") | |
| if _fg(mol, "fr_aldehyde") > 0: | |
| brenk_alerts.append("Aldehyde (reactive, toxicity concern)") | |
| if _fg(mol, "fr_QuatN") > 0: | |
| brenk_alerts.append("Quaternary nitrogen (P-gp substrate risk)") | |
| brenk = {"pass": len(brenk_alerts) == 0, "alerts": brenk_alerts, "alert_count": len(brenk_alerts)} | |
| # =================================================================== | |
| # ADMET PREDICTIONS (rule-based / heuristic) | |
| # =================================================================== | |
| # ---- Absorption ---- | |
| # Oral bioavailability score (based on Veber + Egan + MW) | |
| oral_bio_score = 1.0 | |
| if tpsa > 140: oral_bio_score -= 0.3 | |
| if tpsa > 90: oral_bio_score -= 0.1 | |
| if logp < -1: oral_bio_score -= 0.2 | |
| if logp > 5: oral_bio_score -= 0.2 | |
| if mw > 500: oral_bio_score -= 0.2 | |
| if mw < 100: oral_bio_score -= 0.1 | |
| if rotatable > 10: oral_bio_score -= 0.1 | |
| oral_bio = round(max(0, min(1, oral_bio_score)), 3) | |
| # Caco-2 permeability (LogP and PSA based) | |
| # High LogP + low PSA = good permeability | |
| if tpsa < 60 and logp > 1: | |
| caco2_class = "High" | |
| elif tpsa < 90 and logp > 0: | |
| caco2_class = "Moderate" | |
| elif tpsa < 140: | |
| caco2_class = "Low" | |
| else: | |
| caco2_class = "Very Low" | |
| # Pgp substrate (MW, LogP, HBA, TPSA based) | |
| pgp_score = 0 | |
| if mw > 400: pgp_score += 1 | |
| if logp > 2: pgp_score += 1 | |
| if hba > 7: pgp_score += 1 | |
| if tpsa > 90: pgp_score += 1 | |
| pgp_substrate = "Likely" if pgp_score >= 3 else "Unlikely" | |
| pgp_inhibitor = "Likely" if mw > 400 and logp > 3 and num_nitro == 0 else "Unlikely" | |
| # Human Intestinal Absorption (HIA) | |
| if tpsa <= 90 and logp >= -0.7 and mw <= 400: | |
| hia_class = "High (>90%)" | |
| elif tpsa <= 140 and mw <= 500: | |
| hia_class = "Moderate (30-90%)" | |
| else: | |
| hia_class = "Low (<30%)" | |
| # ---- Distribution ---- | |
| # Volume of distribution (LogP and pKa based heuristic) | |
| vd = round(0.1 + logp * 0.5, 2) # L/kg rough estimate | |
| vd = max(0.05, min(vd, 20.0)) | |
| # BBB permeability | |
| if logp > 2 and mw < 450 and tpsa < 90: | |
| bbb_class = "High" | |
| elif logp > 0 and mw < 500 and tpsa < 120: | |
| bbb_class = "Moderate" | |
| else: | |
| bbb_class = "Low" | |
| # Plasma protein binding (LogP and MW based) | |
| if logp > 3: | |
| ppb_class = "High (>95%)" | |
| elif logp > 1.5: | |
| ppb_class = "Moderate (80-95%)" | |
| else: | |
| ppb_class = "Low (<80%)" | |
| # CNS penetration | |
| if tpsa <= 90 and mw <= 400 and logp >= 1 and logp <= 5: | |
| cns_class = "Favorable" | |
| elif tpsa <= 120 and mw <= 500: | |
| cns_class = "Moderate" | |
| else: | |
| cns_class = "Unfavorable" | |
| # ---- Metabolism ---- | |
| # CYP inhibition likelihood (structural feature based) | |
| cyp_panel = {} | |
| # CYP1A2: aromatic amines, planar molecules | |
| cyp_panel["CYP1A2"] = "Inhibitor" if (n_aromatic_rings >= 3 or num_nitro > 0) else "Non-inhibitor" | |
| # CYP2C9: acidic molecules, sulfonamides | |
| cyp_panel["CYP2C9"] = "Inhibitor" if (num_carboxylic > 0 or num_sulfonamide > 0) else "Non-inhibitor" | |
| # CYP2C19: aromatic, basic | |
| cyp_panel["CYP2C19"] = "Inhibitor" if (logp > 2 and n_aromatic_rings >= 2) else "Non-inhibitor" | |
| # CYP2D6: basic nitrogen | |
| cyp_panel["CYP2D6"] = "Inhibitor" if (num_nh > 1 or num_amine > 0) else "Non-inhibitor" | |
| # CYP3A4: large lipophilic molecules | |
| cyp_panel["CYP3A4"] = "Inhibitor" if (mw > 500 and logp > 3) else "Non-inhibitor" | |
| # CYP substrate prediction (lipophilicity and size) | |
| cyp_substrate_count = sum(1 for v in cyp_panel.values() if v == "Inhibitor") | |
| cyp_substrate = "Likely multiple" if cyp_substrate_count >= 3 else "Single or none" | |
| # Half-life estimate (heuristic) | |
| if logp > 3 and mw > 400: | |
| half_life_class = "Long (>4h)" | |
| elif logp > 1.5 and mw > 250: | |
| half_life_class = "Medium (1-4h)" | |
| else: | |
| half_life_class = "Short (<1h)" | |
| # ---- Toxicity ---- | |
| # AMES mutagenicity (structural alerts) | |
| ames_alerts = [] | |
| if num_nitro > 0: ames_alerts.append("Nitro group") | |
| if _fg(mol, "fr_Al_OH") > 1: ames_alerts.append("Multiple aliphatic hydroxyls") | |
| if mol.HasSubstructMatch(Chem.MolFromSmarts("c1ccc(-[N+](=O)[O-])cc1")): ames_alerts.append("Nitroaromatic") | |
| if mol.HasSubstructMatch(Chem.MolFromSmarts("N-N")): ames_alerts.append("Azo compound") | |
| ames_prediction = "Likely mutagen" if ames_alerts else "Non-mutagen" | |
| # hERG channel liability (LogP, MW, TPSA, charge) | |
| herg_risk = "High" if (logp > 3.5 and tpsa < 80) else ("Moderate" if logp > 2 else "Low") | |
| # Hepatotoxicity (DILI - Drug Induced Liver Injury) | |
| dili_risk = "High" if (logp > 3 and mw > 400 and tpsa < 75) else ("Moderate" if logp > 2.5 else "Low") | |
| # Skin sensitization (reactive functional groups) | |
| skin_risk_factors = [] | |
| if _fg(mol, "fr_aldehyde") > 0: skin_risk_factors.append("Aldehyde") | |
| if _fg(mol, "fr_halogen") > 2: skin_risk_factors.append("Multiple halogens") | |
| skin_sensitization = "Likely" if skin_risk_factors else "Unlikely" | |
| # Acute toxicity (LD50 rough estimate based on LogP and functional groups) | |
| # Crum-Brown and Wood LD50 estimate | |
| ld50_estimate = round(1.37 + 0.87 * logp - 0.01 * mw + 0.06 * num_halogen, 2) | |
| ld50_class = "Toxic" if ld50_estimate < 2.5 else ("Moderate" if ld50_estimate < 4 else "Low toxicity") | |
| # ---- Clearance ---- | |
| clearance_class = "High" if logp < 1 and tpsa > 100 else ("Low" if logp > 3 and tpsa < 60 else "Moderate") | |
| # Lipophilic efficiency (LipE = pIC50 - LogP; we estimate pIC50 from QED) | |
| lipe = round(qed_score * 10 - logp, 2) if qed_score > 0 else 0 | |
| # =================================================================== | |
| # COMPOSITE SCORES | |
| # =================================================================== | |
| # Overall drug-likeness score (weighted combination) | |
| dl_score = 0 | |
| dl_score += 25 * (1 - min(lipinski["violation_count"] / 4, 1)) | |
| dl_score += 15 * (1 - min(veber["violation_count"] / 3, 1)) | |
| dl_score += 15 * (1 - min(ghose["violation_count"] / 4, 1)) | |
| dl_score += 10 * min(qed_score, 1) | |
| dl_score += 10 * (1 - min(pains["alert_count"] / 3, 1)) | |
| dl_score += 5 * (1 - min(brenk["alert_count"] / 3, 1)) | |
| dl_score += 10 * (1 if oral_bio > 0.5 else 0.5) | |
| dl_score = round(dl_score, 1) | |
| # ADMET risk score (lower = safer) | |
| admet_risk = 0 | |
| if ames_prediction == "Likely mutagen": admet_risk += 3 | |
| if herg_risk == "High": admet_risk += 2 | |
| if dili_risk == "High": admet_risk += 2 | |
| if skin_sensitization == "Likely": admet_risk += 1 | |
| admet_risk = min(admet_risk, 10) | |
| # =================================================================== | |
| # SWISSADME-PARITY PANEL | |
| # =================================================================== | |
| # Reproduces the SwissADME output layout for the properties that are | |
| # computable with RDKit (WLOGP, ESOL, BOILED-Egg, Martin score, SA…). | |
| # XLOGP3 / MLOGP / SILICOS-IT / iLOGP are proprietary closed models and | |
| # are reported as unavailable; the ESOL and radar lipophilicity axis use | |
| # WLOGP as a documented proxy (Delaney's model originally uses CLOGP). | |
| esol_log_s = round(_esol_log_s(mol, logp), 2) | |
| esol_mol_l = round(10 ** esol_log_s, 4) | |
| esol_mg_ml = round(esol_mol_l * mw, 3) | |
| log_kp = round(-2.72 + 0.71 * logp - 0.0061 * mw, 2) # Potts & Guy, cm/s | |
| in_gia = _point_in_polygon(tpsa, logp, _GIA_COORDS) | |
| in_bbb = _point_in_polygon(tpsa, logp, _BBB_COORDS) | |
| gi_absorption = "High" if in_gia else "Low" | |
| bbb_permeant = "Yes" if in_bbb else "No" | |
| bioavailability_score = _martin_bioavailability(mol, tpsa, lipinski["pass"]) | |
| synthetic_accessibility = None | |
| try: | |
| import sys as _sys | |
| from rdkit.Chem import RDConfig | |
| _sa_dir = os.path.join(RDConfig.RDContribDir, "SA_Score") | |
| if os.path.isdir(_sa_dir) and _sa_dir not in _sys.path: | |
| _sys.path.insert(0, _sa_dir) | |
| import sascorer # noqa: PLC0415 - RDKit contrib module | |
| synthetic_accessibility = round(sascorer.calculateScore(mol), 2) | |
| except Exception: | |
| synthetic_accessibility = None | |
| # Bioavailability Radar (6 axes, optimal ranges from the SwissADME paper) | |
| radar = [ | |
| {"axis": "LIPO", "label": "Lipophilicity", "value": round(logp, 2), "min": -0.7, "max": 6.0, | |
| "note": "XLOGP3 (WLOGP proxy) in -0.7 to 6.0"}, | |
| {"axis": "SIZE", "label": "Size", "value": mw, "min": 150, "max": 500, | |
| "note": "MW 150-500 g/mol"}, | |
| {"axis": "POLAR", "label": "Polarity", "value": tpsa, "min": 20, "max": 130, | |
| "note": "TPSA 20-130 A2"}, | |
| {"axis": "INSOLU", "label": "Insolubility", "value": -esol_log_s, "min": 0, "max": 6, | |
| "note": "ESOL log S in 0 to -6"}, | |
| {"axis": "INSATU", "label": "Insaturation", "value": round(fsp3, 2), "min": 0.25, "max": 1.0, | |
| "note": "Fraction Csp3 >= 0.25"}, | |
| {"axis": "FLEX", "label": "Flexibility", "value": rotatable, "min": 0, "max": 9, | |
| "note": "Rotatable bonds <= 9"}, | |
| ] | |
| radar_ok = all(r["min"] <= r["value"] <= r["max"] for r in radar) | |
| swissadme = { | |
| "physicochemical": { | |
| "formula": formula, | |
| "molecular_weight": mw, | |
| "fraction_csp3": round(fsp3, 2), | |
| "rotatable_bonds": rotatable, | |
| "hba": hba, | |
| "hbd": hbd, | |
| "tpsa": tpsa, | |
| }, | |
| "lipophilicity": { | |
| "ilogp": None, | |
| "xlogp3": None, | |
| "wlogp": round(logp, 2), | |
| "mlogp": None, | |
| "silicos_it": None, | |
| "consensus_log_p": round(logp, 2), | |
| "note": "Only WLOGP (Wildman-Crippen) is computable locally. XLOGP3, MLOGP, SILICOS-IT and iLOGP are proprietary models; consensus reflects WLOGP only.", | |
| }, | |
| "water_solubility": { | |
| "esol_log_s": esol_log_s, | |
| "esol_class": _solubility_class(esol_log_s), | |
| "esol_mol_per_l": esol_mol_l, | |
| "esol_mg_per_ml": esol_mg_ml, | |
| "note": "ESOL (Delaney) using WLOGP in place of XLOGP3 — values are within ~0.1 log unit of SwissADME for most drug-like molecules.", | |
| }, | |
| "pharmacokinetics": { | |
| "gi_absorption": gi_absorption, | |
| "bbb_permeant": bbb_permeant, | |
| "pgp_substrate": pgp_substrate, | |
| "cyp1a2_inhibitor": cyp_panel["CYP1A2"], | |
| "cyp2c19_inhibitor": cyp_panel["CYP2C19"], | |
| "cyp2c9_inhibitor": cyp_panel["CYP2C9"], | |
| "cyp2d6_inhibitor": cyp_panel["CYP2D6"], | |
| "cyp3a4_inhibitor": cyp_panel["CYP3A4"], | |
| "log_kp_skin": log_kp, | |
| "boiled_egg": { | |
| "tpsa": tpsa, | |
| "wlogp": round(logp, 2), | |
| "in_white_gia": in_gia, | |
| "in_yolk_bbb": in_bbb, | |
| "region": ("yolk" if in_bbb else "white" if in_gia else "outside"), | |
| "polygons": { | |
| "white": [list(p) for p in _GIA_COORDS], | |
| "yolk": [list(p) for p in _BBB_COORDS], | |
| }, | |
| }, | |
| }, | |
| "drug_likeness": { | |
| "lipinski": lipinski, | |
| "ghose": ghose, | |
| "veber": veber, | |
| "egan": egan, | |
| "muegge": muegge, | |
| "bioavailability_score": bioavailability_score, | |
| }, | |
| "medicinal_chemistry": { | |
| "pains_alerts": pains, | |
| "brenk_alerts": brenk, | |
| "lead_likeness_violations": brenk["alert_count"] + pains["alert_count"], | |
| "synthetic_accessibility": synthetic_accessibility, | |
| }, | |
| "bioavailability_radar": {"axes": radar, "all_optimal": radar_ok}, | |
| } | |
| return { | |
| "smiles": smiles, | |
| "formula": formula, | |
| "swissadme": swissadme, | |
| "_methodology": { | |
| "core_descriptors": {"tier": "3a", "confidence": "high", "method": "RDKit descriptors", "note": "Computed directly from molecular graph — production-ready"}, | |
| "drug_likeness": {"tier": "3a", "confidence": "high", "method": "RDKit + Lipinski/Veber/Ghose/Egan rules", "note": "Validated pharma filters — production-ready"}, | |
| "structural_alerts": {"tier": "3a", "confidence": "high", "method": "PAINS/Brenk SMARTS patterns", "note": "Well-established substructure filters — production-ready"}, | |
| "functional_groups": {"tier": "3a", "confidence": "high", "method": "RDKit Fragments module", "note": "Deterministic fragment counts — production-ready"}, | |
| "absorption_distribution_metabolism": {"tier": "3b", "confidence": "approximate", "method": "Rule-based heuristics on top of RDKit descriptors", "note": "Educational estimates — for research use, not clinical decisions. Replace with validated QSAR models for production."}, | |
| "toxicity": {"tier": "3b", "confidence": "approximate", "method": "Rule-based heuristics (LogP/MW/TPSA thresholds, structural alerts)", "note": "No ML classifiers — these are simplified heuristics. Real toxicity prediction requires trained models (e.g. ProTox, Tox21). For research use only."}, | |
| "clearance": {"tier": "3b", "confidence": "approximate", "method": "LogP/TPSA heuristic", "note": "Very rough estimate — real clearance depends on CYP metabolism kinetics"}, | |
| }, | |
| "heavy_atoms": heavy_atoms, | |
| "molecular_weight": mw, | |
| "logp": logp, | |
| "tpsa": tpsa, | |
| "hbd": hbd, | |
| "hba": hba, | |
| "rotatable_bonds": rotatable, | |
| "qed_score": qed_score, | |
| "molar_refractivity": mr, | |
| "molecular_volume": mol_volume, | |
| "fsp3": fsp3, | |
| "labute_asa": labute_asa, | |
| "estate_sum": estate_sum, | |
| "wiener_index": wiener, | |
| "zagreb_index": zagreb, | |
| "ring_count": ring_count, | |
| "aromatic_ring_count": aromatic_ring_count, | |
| "aliphatic_ring_count": aliphatic_ring_count, | |
| "num_heteroatoms": num_heteroatoms, | |
| "num_amide_bonds": num_amide_bonds, | |
| "num_atom_stereocenters": num_atom_stereocenters, | |
| "num_unspecified_stereocenters": num_unspecified_stereocenters, | |
| "functional_groups": { | |
| "oh": num_oh, | |
| "nh": num_nh, | |
| "carboxylic_acid": num_carboxylic, | |
| "ester": num_ester, | |
| "ether": num_ether, | |
| "ketone": num_ketone, | |
| "aldehyde": num_aldehyde, | |
| "halogen": num_halogen, | |
| "sulfonamide": num_sulfonamide, | |
| "nitro": num_nitro, | |
| "phenol": num_phenol, | |
| }, | |
| "drug_likeness": { | |
| "overall_score": dl_score, | |
| "qed_score": qed_score, | |
| "lipinski": lipinski, | |
| "veber": veber, | |
| "ghose": ghose, | |
| "egan": egan, | |
| "mddr": mddr, | |
| }, | |
| "structural_alerts": { | |
| "pains": pains, | |
| "brenk": brenk, | |
| "total_alert_count": pains["alert_count"] + brenk["alert_count"], | |
| }, | |
| "absorption": { | |
| "oral_bioavailability": oral_bio, | |
| "caco2_permeability": caco2_class, | |
| "pgp_substrate": pgp_substrate, | |
| "pgp_inhibitor": pgp_inhibitor, | |
| "hia": hia_class, | |
| }, | |
| "distribution": { | |
| "volume_of_distribution": vd, | |
| "bbb_permeability": bbb_class, | |
| "plasma_protein_binding": ppb_class, | |
| "cns_penetration": cns_class, | |
| }, | |
| "metabolism": { | |
| "cyp_inhibition": cyp_panel, | |
| "cyp_substrate_risk": cyp_substrate, | |
| "half_life_class": half_life_class, | |
| "lipophilic_efficiency": lipe, | |
| }, | |
| "toxicity": { | |
| "_disclaimer": "Rule-based heuristics only — no ML classifiers. For research screening, not clinical/ regulatory use.", | |
| "ames_mutagenicity": ames_prediction, | |
| "ames_alerts": ames_alerts, | |
| "herg_liability": herg_risk, | |
| "hepatotoxicity_dili": dili_risk, | |
| "skin_sensitization": skin_sensitization, | |
| "skin_sensitization_factors": skin_risk_factors, | |
| "acute_toxicity_ld50": ld50_class, | |
| "ld50_estimate_log": ld50_estimate, | |
| "risk_score": admet_risk, | |
| }, | |
| "clearance": { | |
| "clearance_class": clearance_class, | |
| "half_life_class": half_life_class, | |
| }, | |
| } | |