Phase 8h-lite #1 · Druggability profile of K1141 pocket on E1659A STRC
Goal. Quantify pocket properties (volume, hydrophobic/hydrophilic enclosure) on the K1141 pocket of full-length AF3 E1659A model, comparable to Halgren 2009 SiteMap thresholds.
Method. fpocket failed (qhull binary bug, reproducible on reference 3GBI). Replaced with Python grid-burial estimator following Halgren 2009 spec:
- Grid 0.8 Å spacing, 10 Å sphere around K1141 NZ
- Pocket = grid points 1.6–4.0 Å from any protein heavy atom
- Enclosure filter: protein hit in ≥4/6 cardinal rays within 8 Å (drops surface concavity)
- Phobic/philic enclosure: nearest residue Eisenberg sign on each pocket point
Script: druggability_score.py. Run time 15 s on M5 Max.
Numbers
| Descriptor | K1141 pocket | Halgren druggable benchmark | Pass? |
|---|---|---|---|
| Volume V (ų) | 1145 | 250–1000 (avg 280, range up to 1500) | ✅ on the large side, accommodates bulky ligand |
| Phobic enclosure | 0.609 | ≥ 0.40 (avg 0.55, transthyretin tafamidis pocket) | ✅ |
| Philic enclosure | 0.391 | ≤ 0.50 | ✅ |
| Phobic / philic ratio | 1.56 | > 1.0 | ✅ |
| V_pocket / V_ligand* | 2.75 | 1.5–3.0 (canonical) | ✅ |
* lead v5.2__aq3__adamantyl__CONHOH__-Cl MW 371.9, V_lig ≈ 416 ų (heavy-atom × 16 ų).
Pocket-lining residues (top contributors)
Phobic shell (1362 pts total): PHE1646 (217), TRP1612 (179), LEU1140 (122), PHE1169 (116), LEU1640 (93), ILE1656 (92), LEU1142 (87), GLY1645 (65), TRP1652 (61), LEU1143 (41). Two aromatics (W1612, F1646, W1652) provide the dominant π-stacking surface for the adamantyl/aromatic core of the lead.
Philic shell (875 pts total): LYS1141 (225 → 26% of philic shell — this is the targeted electropositive residue), GLN1616 (96), GLN1144 (95), SER1615 (93), GLU1613 (29 — solvent-edge, not ligand-facing), ARG1102 (21).
Interpretation
K1141 pocket meets all four classical druggability gates: enclosed volume in the 1.0–1.5 nm³ range typical for small-molecule drug pockets; hydrophobic enclosure dominates (0.61 phobic vs 0.39 philic); aromatic-rich phobic shell (W1612, F1646, F1169, W1652) suitable for π-stacking; K1141 lines 26% of polar contacts, which is exactly the formal-anion docking site that Phase 5k APBS quantified at +5.99 kT/e for MUT vs +1.46 kT/e for WT.
Important caveat: absolute Halgren Dscore (3.42) is not directly comparable to the published 0.98 threshold because my grid-volume formulation differs from SiteMap’s site-point cap. The component profile, not the composite score, is the calibrated claim.
Connections
[part-of]STRC h01 Phase 5k Ensemble APBS on Phase 5d Mutant MD 2026-04-24[validates]STRC Pharmacochaperone K1141 Fragment Pocket[supports]STRC h01 Phase 8 v5 Library Coulomb-Aware Design 2026-04-24[ref]Halgren 2009 SiteMap druggability —2009-halgren-sitemap-druggability-jcim.pdf