Bio Molecular Descriptors

Version Compatibility

Reference examples tested with: RDKit 2024.09+, numpy 1.26+, pandas 2.2+, map4 1.1+ (MAP4), mhfp 1.9+. Use mapchiral separately when the stereochemistry-aware MAP4C fingerprint is intended.

Before using code patterns, verify installed versions match. If versions differ:

• Python: pip show <package> then help(module.function) to check signatures

If code throws ImportError, AttributeError, or TypeError, introspect the installed package and adapt the example to match the actual API rather than retrying.

Molecular Descriptors

Featurize molecules for similarity search, QSAR, virtual screening, or ML. Fingerprint performance is dataset- and objective-dependent: ECFP4 is a strong drug-like baseline, atom-pair and topological-torsion fingerprints expose longer-range topology, MAP4/MHFP6 target broader chemical-space searches, and 3D conformer-based descriptors are needed when shape and stereochemistry matter.

For canonicalization before featurization, see chemoinformatics/molecular-standardization. For 3D-only descriptors, see chemoinformatics/conformer-generation.

Fingerprint Taxonomy

Decision: For drug-like similarity ranking, start with ECFP4 2048 bit because it is fast and well characterized. MHFP6 outperformed ECFP4 for analog recovery in the benchmark reported by Probst and Reymond (2018), making it a candidate for large, diverse libraries. For scaffold hopping, benchmark ECFP4, AtomPair, TopologicalTorsion, and pharmacophore fingerprints on target-relevant actives and decoys; published comparisons do not support a universal AtomPair advantage (Gardiner et al. 2011; Riniker & Landrum 2013).

Bit vs Count Vectors

from rdkit import Chem
from rdkit.Chem import rdFingerprintGenerator

mol = Chem.MolFromSmiles('CCO')

morgan = rdFingerprintGenerator.GetMorganGenerator(radius=2, fpSize=2048)
ecfp4_bit = morgan.GetFingerprint(mol)
ecfp4_count = morgan.GetCountFingerprint(mol)
ecfp4_sparse = morgan.GetSparseCountFingerprint(mol)

Morgan / ECFP Radius Math

ECFP-X notation: X is the diameter in bonds. RDKit's radius parameter is half of X.

Trade-off: Larger radius captures more specific local environments but increases collisions at fixed nBits. ECFP4 2048 is a common baseline (Rogers & Hahn 2010; Wu et al. 2018). O'Boyle and Sayle (2016) showed that increasing folded-fingerprint length can improve virtual-screening performance, but they did not establish a universal 4096-bit setting or a 1-5% collision rate. Measure collision occupancy and model performance for the dataset; increase nBits or use an unhashed sparse representation when needed.

FCFP vs ECFP

FCFP (Functional-Class) uses RDKit's Morgan feature invariants (donor, acceptor, aromatic, halogen, basic, and acidic) instead of atom identity. Hydrophobe is a family in BaseFeatures.fdef, but it is not one of the default Morgan feature-invariant classes. FCFP trades atom-specificity for functional-equivalence.

ecfp_generator = rdFingerprintGenerator.GetMorganGenerator(radius=2, fpSize=2048)
feature_invariants = rdFingerprintGenerator.GetMorganFeatureAtomInvGen()
fcfp_generator = rdFingerprintGenerator.GetMorganGenerator(
    radius=2, fpSize=2048, atomInvariantsGenerator=feature_invariants)
ecfp4 = ecfp_generator.GetFingerprint(mol)
fcfp4 = fcfp_generator.GetFingerprint(mol)

When to use FCFP4: Scaffold-hopping campaigns, pharmacophore-driven similarity, cross-target activity prediction.

When to use ECFP4: Within-series QSAR, lead optimization, when chemotype identity matters.

3D Descriptors and Conformer Dependence

Conformer-dependent descriptors (asphericity, eccentricity, principal moments of inertia, RDF) require a generated 3D structure. A single conformer may be unrepresentative when the molecule is flexible; measure descriptor variation across a conformer ensemble when the downstream conclusion depends on 3D shape.

Goal: Compute 3D shape descriptors over a conformer ensemble rather than from a single (possibly unrepresentative) conformer.

Approach: Add explicit hydrogens, embed N conformers with ETKDGv3, MMFF-optimize them all, then evaluate the descriptor across each conformer for downstream averaging.

from rdkit.Chem import AllChem, Descriptors3D

mol = Chem.MolFromSmiles('CCCCO')
mol = Chem.AddHs(mol)

params = AllChem.ETKDGv3()
params.randomSeed = 42
conf_ids = AllChem.EmbedMultipleConfs(mol, numConfs=20, params=params)
if not conf_ids:
    raise RuntimeError('ETKDGv3 failed to generate any conformers')
if not AllChem.MMFFHasAllMoleculeParams(mol):
    raise ValueError('MMFF94 parameters are unavailable for this molecule')
optimization_results = AllChem.MMFFOptimizeMoleculeConfs(mol)
if any(status != 0 for status, _ in optimization_results):
    raise RuntimeError('MMFF94 optimization did not converge for every conformer')

asphericities = [Descriptors3D.Asphericity(mol, confId=c) for c in conf_ids]

Decision: For QSAR / ML, choose and document the conformer count using a convergence check on representative molecules. Report the aggregation rule, such as a simple mean or a Boltzmann-weighted average, and the energy model used for any weights.

Partial Charge Methods

from rdkit.Chem import AllChem

AllChem.ComputeGasteigerCharges(mol)
for atom in mol.GetAtoms():
    print(atom.GetIdx(), atom.GetPropsAsDict().get('_GasteigerCharge', None))

Critical: Charge method must match downstream. Gasteiger charges in an AMBER MD run violate the assumptions of the protein force field.

MAP4 and MHFP6 for Diverse Libraries

For libraries spanning drug-like molecules, natural products, peptides, and metabolites, compare ECFP4 with MAP4 or MHFP6 on task-relevant retrieval benchmarks. MAP4 and MHFP6 use MinHash with atom-pair or circular-substructure shingles, but no universal pairwise-similarity range establishes that ECFP4 is saturated for every mixed library.

from mhfp.encoder import MHFPEncoder

encoder = MHFPEncoder(2048)
mhfp6 = encoder.encode_mol(mol, radius=3)

MHFP6 distance is Jaccard on MinHash, not standard Tanimoto. Use MHFPEncoder.distance(fp1, fp2).

Physicochemical Descriptors

Goal: Compute a standard physicochemical descriptor panel for drug-likeness filtering and QSAR features.

Approach: Combine RDKit Descriptors, Lipinski, and QED calls into a single dict so the caller gets MW, LogP, HBD/HBA, TPSA, rotatable bonds, aromatic rings, fraction sp3, and QED in one pass.

from rdkit.Chem import Descriptors, Lipinski, QED

def physchem(mol):
    return {
        'MolWt': Descriptors.MolWt(mol),
        'MolLogP': Descriptors.MolLogP(mol),
        'HBD': Lipinski.NumHDonors(mol),
        'HBA': Lipinski.NumHAcceptors(mol),
        'TPSA': Descriptors.TPSA(mol),
        'RotBonds': Lipinski.NumRotatableBonds(mol),
        'AromRings': Lipinski.NumAromaticRings(mol),
        'FractionCSP3': Descriptors.FractionCSP3(mol),
        'QED': QED.qed(mol),
    }