Junior B.
7c6cef1aef
§12.4 pushed to its limit. Meeko ligand prep + in-place symmetry RMSD (spyrmsd, not obrms) on clean HDAC2/vorinostat: 7.9A -> 4.76A. Prep and metric mattered, but still FAIL. Residual cause is fundamental: vorinostat binds via hydroxamate-Zn chelation and Vina has no metal-coordination term. Real finding: sickle's druggable targets bind via non-classical chemistry classical docking handles poorly -- Hb (covalent), PKR (allosteric+cofactor), HDAC (Zn chelation). Vina is the wrong tool for this target landscape. Redirect: data-driven AF3-class co-folding (Boltz-2/Chai-1/DiffDock) handles these modes -- the indicated next tool, gated by the 24GB local memory ceiling (cloud GPU needed). The "GPU breaks all-local" §12.6 prediction is now the binding constraint of the track. Adds: scripts/dock_production.py; deps meeko, spyrmsd, gemmi. Co-Authored-By: Claude Opus 4.8 (1M context) <noreply@anthropic.com>
84 lines
3.6 KiB
Python
84 lines
3.6 KiB
Python
"""Push docking to credibility: Meeko ligand prep + in-place spyrmsd, on the clean HDAC2 target.
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Isolates the two cheap suspects behind the 7.9 A redocking failure:
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1. ligand prep — replace bare obabel --gen3d with Meeko (correct rotatable bonds / AD typing)
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2. RMSD metric — replace obrms (superimposes) with spyrmsd in-place, symmetry-corrected
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Receptor reused (obabel-protonated 4LXZ with catalytic Zn kept). If redock RMSD drops <2 A, the
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docking pipeline is validated and the earlier failure was prep+metric, not docking itself.
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"""
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from __future__ import annotations
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import subprocess
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from pathlib import Path
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import numpy as np
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from rdkit import Chem, RDLogger
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from rdkit.Chem import AllChem
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from meeko import MoleculePreparation, PDBQTWriterLegacy
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from spyrmsd import io as spyio, rmsd as spyrmsd
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import sys
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sys.path.insert(0, str(Path(__file__).resolve().parent.parent))
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from scripts.dock_positive_controls import STRUCT, VINA, WORK, pubchem_smiles # noqa: E402
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from scripts.dock_validate import dock_pose, extract_crystal_ligand # noqa: E402
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RDLogger.DisableLog("rdApp.*")
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PDB, RES, DRUG = "4LXZ", "SHH", "vorinostat"
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def prep_receptor_keep_zn() -> tuple[Path, np.ndarray, np.ndarray]:
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atoms, lig, chosen = [], [], None
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for ln in (STRUCT / f"{PDB}.pdb").read_text().splitlines():
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if ln.startswith("ATOM") or (ln.startswith("HETATM") and ln[17:20].strip() == "ZN"):
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atoms.append(ln)
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elif ln.startswith("HETATM") and ln[17:20].strip() == RES:
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key = (ln[21], ln[22:26]); chosen = chosen or key
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if key == chosen:
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lig.append(ln)
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recpdb = WORK / f"{PDB}_rec.pdb"; recpdb.write_text("\n".join(atoms) + "\nEND\n")
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recpdbqt = WORK / f"{PDB}_rec.pdbqt"
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subprocess.run(["obabel", str(recpdb), "-O", str(recpdbqt), "-xr", "-p", "7.4"], capture_output=True)
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xyz = np.array([[float(l[30:38]), float(l[38:46]), float(l[46:54])] for l in lig])
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return recpdbqt, xyz.mean(0), np.clip((xyz.max(0) - xyz.min(0)) + 8, 16, 26)
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def meeko_ligand(smiles: str) -> Path:
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mol = Chem.AddHs(Chem.MolFromSmiles(smiles))
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AllChem.EmbedMolecule(mol, randomSeed=0xC0FFEE)
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AllChem.MMFFOptimizeMolecule(mol)
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setups = MoleculePreparation().prepare(mol)
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pdbqt, ok, err = PDBQTWriterLegacy.write_string(setups[0])
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if not ok:
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raise RuntimeError(f"meeko ligand prep failed: {err}")
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out = WORK / f"lig_{DRUG}_meeko.pdbqt"; out.write_text(pdbqt)
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return out
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def inplace_rmsd(crystal_pdb: Path, docked_pdbqt: Path) -> float:
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cref = WORK / "xtal.sdf"; cdoc = WORK / "docked.sdf"
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subprocess.run(["obabel", str(crystal_pdb), "-O", str(cref)], capture_output=True)
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subprocess.run(["obabel", str(docked_pdbqt), "-O", str(cdoc), "-f", "1", "-l", "1"], capture_output=True)
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ref, mol = spyio.loadmol(str(cref)), spyio.loadmol(str(cdoc))
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ref.strip(); mol.strip()
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r = spyrmsd.rmsdwrapper(ref, mol, symmetry=True, minimize=False)
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return float(r[0] if isinstance(r, (list, tuple, np.ndarray)) else r)
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def main() -> None:
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rec, center, size = prep_receptor_keep_zn()
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smi = pubchem_smiles(DRUG)
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lig = meeko_ligand(smi)
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print(f"meeko ligand pdbqt: {lig.name}; box center {center.round(1)} size {size.round(1)}")
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pose = dock_pose(rec, lig, center, size) # writes WORK/redock_out.pdbqt
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raw = WORK / "redock_out.pdbqt"
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xtal = extract_crystal_ligand(PDB, RES)
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rmsd = inplace_rmsd(xtal, raw)
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verdict = "PASS (<2A)" if rmsd < 2 else ("MARGINAL (<3A)" if rmsd < 3 else "FAIL")
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print(f"\nvorinostat -> HDAC2 redock | in-place spyrmsd RMSD = {rmsd:.2f} A {verdict}")
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print("(prior obabel-ligand + obrms gave 7.9 A)")
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if __name__ == "__main__":
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main()
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