Virtual Screening

Screen compound libraries against protein targets using molecular docking.

Receptor Preparation

from rdkit import Chem
from rdkit.Chem import AllChem
import subprocess

def prepare_receptor(pdb_file, output_pdbqt, remove_waters=True, add_hydrogens=True):
    '''
    Prepare protein for docking.
    Steps: Remove waters -> Add hydrogens -> Assign charges -> PDBQT
    '''
    # Read PDB
    with open(pdb_file) as f:
        lines = f.readlines()

    # Remove waters if requested
    if remove_waters:
        lines = [l for l in lines if not l.startswith(('HETATM', 'CONECT'))
                 or 'HOH' not in l]

    # Write cleaned PDB
    clean_pdb = pdb_file.replace('.pdb', '_clean.pdb')
    with open(clean_pdb, 'w') as f:
        f.writelines(lines)

    # Use Open Babel for conversion (adds hydrogens and charges)
    subprocess.run([
        'obabel', clean_pdb,
        '-O', output_pdbqt,
        '-p', '7.4',  # Add hydrogens at pH 7.4
        '--partialcharge', 'gasteiger'
    ], check=True)

    return output_pdbqt

Ligand Preparation

from rdkit import Chem
from rdkit.Chem import AllChem

def prepare_ligand(smiles, output_pdbqt):
    '''
    Prepare ligand for docking.
    Steps: Generate 3D -> Minimize -> Assign charges -> PDBQT
    '''
    mol = Chem.MolFromSmiles(smiles)
    mol = Chem.AddHs(mol)

    # Generate 3D conformer (ETKDGv3 is default in modern RDKit)
    AllChem.EmbedMolecule(mol, AllChem.ETKDGv3())

    # Minimize with MMFF
    AllChem.MMFFOptimizeMolecule(mol)

    # Write to MOL file
    mol_file = output_pdbqt.replace('.pdbqt', '.mol')
    Chem.MolToMolFile(mol, mol_file)

    # Convert to PDBQT with Open Babel
    subprocess.run([
        'obabel', mol_file,
        '-O', output_pdbqt,
        '--partialcharge', 'gasteiger'
    ], check=True)

    return output_pdbqt

Docking with Vina

from vina import Vina

def dock_ligand(receptor_pdbqt, ligand_pdbqt, center, box_size, exhaustiveness=8):
    '''
    Dock a single ligand using AutoDock Vina 1.2.

    Args:
        receptor_pdbqt: Prepared receptor file
        ligand_pdbqt: Prepared ligand file
        center: (x, y, z) center of binding site
        box_size: (x, y, z) box dimensions (Angstroms)
        exhaustiveness: Search thoroughness (8=quick, 32=production, 64=thorough)
    '''
    v = Vina(sf_name='vina')
    v.set_receptor(receptor_pdbqt)
    v.set_ligand_from_file(ligand_pdbqt)

    # Define search space
    # Box size generally < 30x30x30 Angstroms
    v.compute_vina_maps(center=center, box_size=box_size)

    # Dock
    v.dock(exhaustiveness=exhaustiveness, n_poses=10)

    # Get results
    energies = v.energies()  # List of (affinity, rmsd_lb, rmsd_ub)
    poses = v.poses()  # PDBQT string of all poses

    return energies, poses

# Example usage
# center = (10.0, 20.0, 30.0)  # Binding site center
# box = (20, 20, 20)  # Box size in Angstroms
# energies, poses = dock_ligand('receptor.pdbqt', 'ligand.pdbqt', center, box)

Virtual Screening Pipeline

import os
from pathlib import Path
from vina import Vina
import pandas as pd

def virtual_screen(receptor_pdbqt, ligand_smiles_dict, center, box_size,
                   output_dir, exhaustiveness=8, n_poses=3):
    '''
    Screen compound library against receptor.

    Args:
        receptor_pdbqt: Prepared receptor
        ligand_smiles_dict: Dict of {name: smiles}
        center: Binding site center
        box_size: Search box size
        output_dir: Directory for output files
        exhaustiveness: Search thoroughness
        n_poses: Number of poses to save per ligand
    '''
    Path(output_dir).mkdir(parents=True, exist_ok=True)

    v = Vina(sf_name='vina')
    v.set_receptor(receptor_pdbqt)
    v.compute_vina_maps(center=center, box_size=box_size)

    results = []

    for name, smiles in ligand_smiles_dict.items():
        try:
            # Prepare ligand
            ligand_pdbqt = f'{output_dir}/{name}.pdbqt'
            prepare_ligand(smiles, ligand_pdbqt)

            # Dock
            v.set_ligand_from_file(ligand_pdbqt)
            v.dock(exhaustiveness=exhaustiveness, n_poses=n_poses)

            energies = v.energies()
            best_affinity = energies[0][0] if energies else None

            # Save poses
            if energies:
                pose_file = f'{output_dir}/{name}_poses.pdbqt'
                v.write_poses(pose_file, n_poses=n_poses)

            results.append({
                'name': name,
                'smiles': smiles,
                'affinity_kcal_mol': best_affinity,
                'poses_file': pose_file if energies else None
            })

        except Exception as e:
            print(f'Failed for {name}: {e}')
            results.append({
                'name': name,
                'smiles': smiles,
                'affinity_kcal_mol': None,
                'error': str(e)
            })

    results_df = pd.DataFrame(results)
    results_df = results_df.sort_values('affinity_kcal_mol')

    return results_df

Binding Site Definition

def find_binding_site(receptor_pdb, ligand_pdb=None, padding=5.0):
    '''
    Define binding site from co-crystallized ligand or protein center.

    Args:
        receptor_pdb: Protein PDB file
        ligand_pdb: Optional co-crystallized ligand
        padding: Angstroms to add around ligand
    '''
    if ligand_pdb:
        # Center on ligand
        from rdkit import Chem
        mol = Chem.MolFromPDBFile(ligand_pdb)
        conf = mol.GetConformer()
        coords = [conf.GetAtomPosition(i) for i in range(mol.GetNumAtoms())]

        x = [c.x for c in coords]
        y = [c.y for c in coords]
        z = [c.z for c in coords]

        center = (sum(x)/len(x), sum(y)/len(y), sum(z)/len(z))
        box_size = (max(x)-min(x)+2*padding, max(y)-min(y)+2*padding, max(z)-min(z)+2*padding)
    else:
        # Use protein center (not recommended)
        center = (0, 0, 0)
        box_size = (30, 30, 30)

    return center, box_size

Related Skills

• molecular-io - Load and convert molecules
• admet-prediction - Filter before docking
• structural-biology/structure-io - Protein structure handling
• structural-biology/modern-structure-prediction - Generate targets