STRC Research

STRC h01 Phase 3c v3b + 5d Delivery 2026-04-24

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STRC h01 Phase 3c v3b + 5d Delivery 2026-04-24

Two compute deliverables landed overnight: the 12k-ligand fenamic+covalent ensemble dock (Phase 3c v3b + 6b) and the full-length E1659A mutant MD (Phase 5d). Read together they set the chemistry ceiling and the mutant-pocket gate for everything downstream.

Phase 3c v3b + 6b — ensemble dock result

  • Library: 12,253 ligands (8 cores × 57 N-aryl subs × 5 acid bioisosteres × 8 ring subs; + 6 covalent warheads on 8 cores × 10 hot N-aryls × 2 acid bioisosteres)
  • Ensemble: 5 k-means-selected Phase 5a WT-snap receptor conformers, Stage 1 on snap_008 (exh=8), Stage 2 top-50 × 5 conformers (exh=16)
  • Verdict: 0 GREEN / 29 YELLOW / 21 RED — 0 covalent GREENs, 0 non-covalent GREENs
  • Ceiling: top mean ΔG = −7.28 kcal/mol (Kd ≈ 4.57 µM, bound-fraction@10 µM = 0.686, f_PC = 0.343)
  • Completed 2026-04-24 ~04:03 UTC (PID 73601 exited clean; main JSON + checkpoint JSON written; docking_runs/3c_v3/stage1 24,192 entries, stage2 502 entries)

Top YELLOW cluster — structurally tight:

  1. nc__3-amino-benzofuran-2-COOH__1-naphthyl__CONHOH__-CF3 — mean ΔG −7.28, σ 0.69, Kd 4.57 µM
  2. nc__3-amino-benzofuran-2-COOH__1-naphthyl__CONHSO2Me__-CF3 — mean ΔG −7.28, σ 0.66, Kd 4.58 µM
  3. nc__3-amino-benzoic__4-F-biphenyl__tetrazole__-CF3 — mean ΔG −7.24, σ 0.62, Kd 4.87 µM
  4. nc__3-amino-benzofuran-2-COOH__4-F-biphenyl__tetrazole__-Me — mean ΔG −7.23, σ 0.74, Kd 4.99 µM
  5. nc__3-amino-benzofuran-2-COOH__8-quinolinyl__CONHOH__-CF3 — mean ΔG −7.22, σ 0.58, Kd 5.06 µM

Scaffold signal — top-10 clusters on:

  • Body: 3-amino-benzofuran-2-COOH (7/10) or 2-amino-quinoline-3 (3/10) — benzofuran-2-COOH dominant
  • Tail: 1-naphthyl / 4-F-biphenyl / 8-quinolinyl / 3,5-diMe-phenyl
  • Acid bioisostere: CONHOH hydroxamic ≈ tetrazole ≈ CONHSO₂Me (sulfonamide)
  • Ring sub: −CF₃ dominant; pocket lipophilic

Cross-read vs v2 expanded (2026-04-23): best v2 non-fenamic Kd was 30 µM (niflumic/flufenamic/sulfasalazine). v3b pushed the ceiling 6.6× lower Kd by replacing fenamic body with 3-amino-benzofuran-2-COOH — confirms the fenamic scaffold was the bottleneck per STRC h01 Fenamic Scaffold Tox Audit 2026-04-23. But 4.6 µM Kd / f_PC 0.34 still falls short of the Misha Compound-Het Therapy Stack Model adjunct threshold (f_PC ≥ 0.30 enters MILD-MODERATE but below NORMAL at 0.5). Adjunct-lever status holds.

Phase 5d — E1659A full-length MD result

  • Target: AF3-predicted full-length E1659A STRC (job3-mutant.cif), chain A, 1,775 residues — mutations verified pre-run (K1141=LYS, E1659=ALA)
  • System: 651,437 atoms solvated (TIP3P + 0.15 M NaCl), AMBER14SB, PME, HBond constraints, 2 fs step
  • Thermostat: 310 K, 1.0 bar
  • Trajectory: 2 ns production, 20 snapshots (short-production delivery, not the planned 10 ns)
  • Performance: 14.06 ns/day extrapolated on OpenMM OpenCL Metal — 10 ns projection 17.1 h wall; 2 ns shipped at 3.4 h wall
  • Artifacts: artifacts/phase5d_snapshots/snap_000..019.pdb; pharmacochaperone_phase5d_e1659a_md.json
  • Completed 2026-04-23 23:11 HKT (PID 28875 exited clean)

Gap closed: all prior Phase 5a/5b/5c trajectories were on WT Ultra-Mini (residues 594–1294) which physically excludes residue 1659. Phase 5d is the first MD on the actual disease target.

Caveat: 2 ns is sufficient for sidechain relaxation and local pocket equilibration but below the ≥10 ns normally wanted for backbone ensemble averaging. K1141 pocket geometry assessment via 5e re-dock is appropriate at this trajectory length; full cryptic-pocket search on mutant would need a re-run.

Cross-inference — what v3b + 5d jointly gate

v3b’s 29 YELLOWs are all docked into WT Phase 5a snapshots. Two live questions the Phase 5e re-dock answers:

  1. Does K1141 pocket geometry survive E1659A mutation? 5a pocket centre was (−22.027, −18.547, 2.215). 5e derives box centre per-snapshot from K1141 Cα + pocket ring residues (1135, 1137, 1165, 1167, 1175), keeping 18 Å box.
  2. Do the v2 fenamic hits + legacy leads still bind at Kd ≈ 30–70 µM on the mutant? If ΔΔG_mut−WT > +1 kcal/mol across the shortlist, the pocket shifted meaningfully and v3b YELLOWs are at risk.

5e as written re-docks LEGACY_LEADS (5 Phase 4b leads) + V2_HITS (5 fenamic + tafamidis-analog) = 11 ligands × 20 mutant snapshots × Vina exh=16 — NOT the v3b YELLOWs (script was scaffolded pre-v3b delivery). 5e output is a pocket-geometry probe, not a v3b validation. If pocket is stable on 5e, defer dedicated v3b-on-mutant re-dock as Phase 5f (queued) or accept WT ensemble as adequate and advance to Phase 3c v4 fragment-growing.

Decision — next-step fork

Live options post-v3b + 5d:

  1. Phase 5e mutant-ensemble re-dock (≈15 min wall, 11 ligands × 20 snaps) — launch now: cheapest pocket-stability gate; required before trusting any WT-ensemble docking downstream.
  2. Phase 3c v4 fragment-growing on v3b YELLOW scaffolds — medchem step: grow 3-amino-benzofuran-2-COOH body with polar tail substituents to pull f_PC into 0.5+ territory. Wait for 5e verdict.
  3. Phase 5f v3b-top-29-on-mutant re-dock — conditional on 5e pocket-shift verdict; if pocket shifts, run; if stable, skip.
  4. Phase 6d new warhead class — YAGNI for now; v3b already covered 6 reversible-covalent Lys warheads and landed 0 GREEN covalent hits.

Launching (1) Phase 5e. v4 fragment-growing queues behind 5e verdict.

Ranking delta

Tier A held. mech 3 / deliv 4 / misha_fit 4 all held.

  • v3b did not clear chemistry-limited RED from Phase 3c v2b (0 GREEN). It pushed the chemistry ceiling 6.6× lower Kd (from 30 µM fenamic → 4.6 µM benzofuran-COOH), confirming the STRC h01 Fenamic Scaffold Tox Audit 2026-04-23 pivot was correct. Chemistry now at f_PC = 0.34 vs 0.30 MILD-MODERATE threshold per Misha Compound-Het Therapy Stack Model — crosses adjunct threshold by +0.04, still short of NORMAL (0.50).
  • 5d closed the WT-vs-mutant gap — Phase 5e re-dock on the actual disease target is now unblocked.
  • Pharmacochaperone monotherapy-to-NORMAL claim remains out of reach on current library. Adjunct-lever framing intact.
  • next_step: “Phase 3c v3b dock + 5d E1659A MD running” → “Phase 5e mutant re-dock running (pocket stability gate for v3b YELLOWs); then Phase 3c v4 fragment-grow on 3-amino-benzofuran-2-COOH scaffold”
  • active_runs: cleared (both PIDs dead); 5e added on launch.

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