STRC Research

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Phase 5m TRPM4 τRAMD — FINAL result (2026-04-26 14:50 UTC)

Status: PRODUCTION COMPLETE

All 6 replicas (2 ligands × 3 replicas) finished. Process PID 45852 exited cleanly. Final ranking written.

Headline result

Ligandτ_TRPM4 replicas (ps)τ_TRPM4 medτ_TRPM4 meanστ_STRC medτ_TRPM4/τ_STRC medτ_TRPM4/τ_STRC mean
adamantyl_CONHOMe_-Cl (LEAD)15.8, 19.9, 53.419.929.716.815.81.26×1.52×
adamantyl_CONHOH_-Cl (mech-anchor)18.8, 17.0, 15.517.017.11.315.71.08×1.11×

Verdict

Phase 5p activation gate: τ_TRPM4 / τ_STRC > 5× required for kinetic-selectivity claim. Result: 1.08–1.52× — both candidates FAIL by ≥3× margin.

Kinetic-selectivity rescue at the cross-target level is falsified for both v5.2 LEAD and mech-anchor. This is the actual measured number that Phase 5m within-STRC spread of 1.7× had already mathematically bounded (predicted ceiling < 3.4×; measured 1.08–1.52×, well within ceiling). The bound is not just internally consistent — it predicts cross-target behavior accurately.

Per-replica notes

LEAD CONHOMe_-Cl: wide spread σ=16.8 ps, dominated by replica_02 (τ=53.4 ps, 3.4× the others). Suggests TRPM4 has a metastable secondary mode that the LEAD occasionally finds. This is interesting but does not move the verdict — even mean τ (29.7 ps) is well below 5×. Worth a trajectory inspection (RMSD + contact-map for replica_02 frames 7900–26700) for paper-figure annotation.

Mech-anchor CONHOH_-Cl: tight spread σ=1.3 ps. All three replicas converge at τ ~ 16-19 ps, matching STRC binding kinetics nearly perfectly. The hydroxamic acid head is mechanically isotropic across STRC and TRPM4 — neither pocket can discriminate it.

Implications

  1. v5.2 family is class-bounded for selectivity. No path to >5× via head-group substitution within scoped chemistry. Phase 5p v5.3 acyl-sulfonamide pipeline is affinity-only lead carry-forward, not selectivity rescue.
  2. TRPM4 has a metastable mode (replica_02). Worth understanding mechanistically — could point to a TRPM4-specific anti-target binding pocket that future ZBG-design rounds need to avoid rather than exploit.
  3. The within-target / cross-target connection is now empirically validated. Phase 5m’s mathematical bound (within-STRC spread × n = max cross-target ratio) is correct on this chemistry class. Future kinetic-selectivity claims should pre-screen on within-target spread before committing to cross-target τRAMD.

Pending compute

  • TRPM4 dock for v5.3 acyl-sulfonamide top-3 (currently no pose in poses_8g/). Needs a fresh Vina dock against 8RD9_receptor.pdbqt then full TRPM4 τRAMD on 1-indanyl_SO2Me-Cl (Phase 5q top candidate). ~1 hr Vina + ~3 hr τRAMD = 4 hr next-session compute. Tests whether sulfonamide head class breaks the 1.7× spread bound.
  • Trajectory analysis on replica_02 — mdtraj RMSD + contacts. ~30 min CPU.
  • Paper Figure 3 draft — three-row consensus: STRC τRAMD + TRPM4 τRAMD + ratio + Phase 5p gate threshold horizontal line. Matplotlib script ~30 min.

Connections

Graph View