Pharmacophore Modeling

A pharmacophore defines the minimum set of 3D chemical features — their types, spatial arrangement, and tolerance spheres — required for biological activity. Used for scaffold hopping, virtual screening, and SAR hypothesis generation.

When to Use This Skill

• Derive pharmacophore from a co-crystal structure (structure-based)
• Extract common features from a set of active ligands (ligand-based)
• Screen a compound library for pharmacophore matches (VS)
• Compute pharmacophore fingerprints for similarity searching
• Identify scaffold-hopping opportunities (2D-diverse but 3D-similar)
• Validate binding mode hypotheses against active/inactive SAR data

Feature Types

Feature	Code	SMARTS definition (simplified)
H-bond donor	HBD	[N!H0,O!H0,n!H0]
H-bond acceptor	HBA	[N,O,F,n,o,s] (lone pairs)
Aromatic	AR	any aromatic ring
Hydrophobic	HYD	[c,s,C,S,Br,I,Cl] non-polar
Positive ionizable	POS	[NH2,NH3+,guanidine,amidine]
Negative ionizable	NEG	[COOH,SO3H,PO4H,COO-]
Exclusion volume	XV	regions sterically forbidden

Quick Start

from rdkit import Chem
from rdkit.Chem import AllChem, MolStandardize
from rdkit.Chem.Pharm3D import Pharmacophore, EmbedLib
from rdkit.Chem import rdMolChemicalFeatures

# Load feature factory (FDEF file bundled with RDKit)
import os
from rdkit import RDConfig
fdefName = os.path.join(RDConfig.RDDataDir, 'BaseFeatures.fdef')
factory = rdMolChemicalFeatures.BuildFeatureFactory(fdefName)

# Get features from a molecule
mol = Chem.MolFromSmiles('c1ccc(cc1)C(=O)O')  # benzoic acid
feats = factory.GetFeaturesForMol(mol)
for feat in feats:
    print(f"{feat.GetFamily():12s} {feat.GetType():20s} atoms={list(feat.GetAtomIds())}")

Router — What to Read

Task	Reference
Feature types, SMARTS, exclusion volumes, RDKit FDEF format	references/features-theory.md
Pharm2D fingerprints (Gobbi), Pharm3D matching, feature factory	references/rdkit-pharmacophore.md
Derive pharmacophore from protein-ligand co-crystal / interactions	references/structure-based.md
Common-feature pharmacophore from a set of active ligands	references/ligand-based.md
Pharmacophore VS workflow: conformer gen, hit scoring, enrichment	references/vs-workflow.md

Software

Tool	Install	Role
RDKit	conda install -c conda-forge rdkit	2D/3D pharmacophore (built-in)
ProLIF	pip install prolif	interaction fingerprints (→ features)
PLIP	pip install plip	protein-ligand interaction profiler
shape-it	conda install -c conda-forge shape-it	shape + pharmacophore overlay
Pharmit	web: pharmit.csb.pitt.edu	pharmacophore search (free web)

Related Skills

• rdkit — conformer generation, substructure, 2D fingerprints
• docking — binding poses used to derive structure-based pharmacophore
• mdanalysis — dynamic pharmacophore from MD trajectories
• daylight-theory — SMARTS syntax for custom feature FDEF files