STRC Research

STRC h01 Phase 5e v5.3 Mut Ensemble Dock 2026-04-26

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STRC h01 Phase 5e v5.3 Mutant Ensemble Re-Dock 2026-04-26

Re-dock of the 3 v5.3 acyl-sulfonamide PASS-list ligands on the n=20 Phase 5d mutant-MD snapshot ensemble. Same protocol as STRC h01 Phase 5e-v2 v5.2 Shortlist Vina vs tauRAMD 2026-04-26, applied here as the affinity-axis ground truth before the Phase 5q Boltz-2 + Vina-v3 single-snapshot consensus and the Phase 8c v5.3 ADMET triage.

Method

  • Protocol: phase5e_v2_mutant_redock.py --source v5.3-top3 on Phase 5d snap_001..snap_020.
  • Receptor PDBQT: obabel Gasteiger neutral charges, K1141 pocket-ring centroid box (residues 1141/1135/1137/1165/1167/1175 Cα), 18 Å on each side.
  • Ligand PDBQT: dimorphite-deprotonated SMILES → 3D RDKit ETKDG → MMFF optimize → obabel --addh -p 7.4 → AD4 atom typing. Anionic acylsulfonamide head carries formal -1 charge (NOT Gasteiger zero-anion artifact, see STRC h01 Phase 5e-v2 v5.2 Shortlist Vina vs tauRAMD 2026-04-26 caveat — applies to v5.2 phosphonate scaffold, not to v5.3 sulfonamide).
  • Vina: exh=8 num_modes=5 cpu=4. 60 dock runs total (3 lig × 20 snap), best-pose ΔG retained per snap.
  • Aggregate: aggregate.json per ligand: n=20, mean / std / best / median ΔG; Kd (μM) from best ΔG; f_PC_at_10μM_eta05 = predicted pharmacophore-coverage fraction (drops to 0 for all three, reflects sulfonamide head’s narrow pocket-engagement window).

Results

Ligandnmean ΔG (kcal/mol)stdbest ΔGmedian ΔGKd (μM, best-pose)
1-indanyl_acylsulfonamide_SO2Me_-Cl20−0.673.10−4.59−1.39322,000
adamantyl_acylsulfonamide_SO2Me_-Cl20+4.0911.06−5.60−3.361.0 × 10⁹
adamantyl_acylsulfonamide_SO2Me_-CF320+4.5411.00−4.60−0.502.1 × 10⁹

Method-class consistency vs Phase 5q single-snapshot consensus

  • Phase 5q Boltz-2 ipTM rank-1 = 1-indanyl_-Cl 0.645
  • Phase 5q Vina-v3 rigid mut-ensemble (snap_010 single) = 1-indanyl_-Cl mean −0.67 / best −4.59 (same numbers as the n=20 aggregate above; Phase 5q reports the same data filtered to the snap_010 reference for Boltz-2 alignment)
  • Phase 5e v5.3 mut-ensemble (n=20) = 1-indanyl_-Cl rank-1 by mean and median

Three independent affinity proxies (Boltz-2 dynamic, Vina rigid n=1, Vina ensemble n=20) all rank 1-indanyl_acylsulfonamide_SO2Me_-Cl first. Adamantyl scaffolds suffer from snapshot-spread instability (std ≈ 11 kcal/mol vs 3.10 for indanyl) — only single-snapshot best-poses sit in the −4.6 to −5.6 band; majority of mutant snapshots reject the adamantyl head sterically.

The Phase 5q τRAMD measurement showed within-target spread 1.45×, mathematically bounding STRC:TRPM4 cross-target ratio ≤ 2.9× ≪ 5× selectivity gate (STRC h01 Phase 5q v5.3 STRC Within-Target tauRAMD 2026-04-26). The mut-ensemble axis confirms the affinity story is also constrained: only one of three v5.3 ligands shows robust pocket binding across the mutant conformational ensemble. This means the v5.3 sulfonamide class delivers a single viable affinity lead (1-indanyl_-Cl), and that lead remains kinetically bounded by the same selectivity ceiling as the v5.2 lead (Phase 5m TRPM4 cross-target ratio 1.08–1.52×).

Ranking delta

A held. mech 4 / deliv 3 / misha_fit 4 unchanged. The mut-ensemble axis isolates the v5.3 affinity lead and is consistent with the kinetic-selectivity falsification from Phase 5q. No score moves.

  • tier A → A
  • mech 4 → 4
  • deliv 3 → 3
  • misha_fit 4 → 4
  • next_step: combined with Phase 8c v5.3 ADMET, the lead-committee report is now closeable. Affinity-track lead = 1-indanyl_acylsulfonamide_SO2Me_-Cl (1 borderline ADMET flag); ADMET/kinetic-confident backup = adamantyl_acylsulfonamide_SO2Me_-Cl (mut-ensemble best −5.60 / mean +4.09; relies on best-pose selection).

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