Pharmacophore

Skill Kdevos12/ALKYL/skills/pharmacophore

Claude Plugin for CompChem , Drug Discovery & Organic Chemistry reasoning

Install

npx -y skills add Kdevos12/ALKYL --skill pharmacophore

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Use when working with pharmacophore modeling for drug discovery. Covers feature types (HBD/HBA/AR/HYD/POS/NEG), RDKit 2D/3D pharmacophore fingerprints and matching (Pharm2D, Pharm3D, ChemicalFeatures), structure-based pharmacophore from protein-ligand complexes, ligand-based pharmacophore from active sets, and pharmacophore-based virtual screening workflows.

SKILL.md

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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