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Phase 2 screen pilot: HDAC2 recovers the inhibitor class (P>=0.99)

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Add the `screen` entrypoint (parallel ~10-wide, cached weights) and run a
24-drug pilot vs HDAC2 (+Zn), ranked by Boltz-2 P(binder). ~$1.3.

Result (recovery test at scale): top 9 are ALL HDAC inhibitors
(trichostatin-A/vorinostat/panobinostat/belinostat/scriptaid/mocetinostat/
entinostat/apicidin >=0.99; valproic-acid 0.91), clean drop-off to
hydroxyurea 0.78 and non-HDAC drugs to dexamethasone 0.03. Captures the
structure-activity gradient (hydroxamates > weak fatty-acid > non-HDAC).

Honest false negative: romidepsin (potent HDAC inhibitor) ranks low (0.43)
-- it's a depsipeptide PRODRUG co-folding doesn't model. Screen mishandles
non-standard chemotypes.

Screening pipeline validated; next is the full 300-drug discovery run.
max_containers=10 (parallel safe once weights cached).

Co-Authored-By: Claude Opus 4.8 (1M context) <noreply@anthropic.com>
This commit is contained in:
Junior B.
2026-06-24 22:23:01 +02:00
parent 907a39aaba
commit 0535886ce6
3 changed files with 96 additions and 3 deletions
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docs/structure_binding_notes.md
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@@ -141,7 +141,27 @@ the exact Zn-chelation case Vina was off by 7.9 A. HDAC2 is now validated on BOT
perfect, metal slightly less). The structure-binding modality is comprehensively validated on its
decisive metal-coordination case.
## Step 6 — Phase 2 screen pilot (HDAC2): recovers the inhibitor class decisively (2026-06-24)
`modal run gpu/modal_app.py::screen --limit 24` — co-fold 24 drugs vs HDAC2 (+Zn), parallel
(~10-wide, cached weights), ranked by P(binder). ~$1.3.
**Top 9 = all HDAC inhibitors** (trichostatin-A, vorinostat, panobinostat, belinostat, scriptaid,
mocetinostat, entinostat, apicidin all P≥0.99; valproic-acid 0.91), then a clean drop to
hydroxyurea 0.78 and non-HDAC drugs sinking to dexamethasone 0.03. The model captures the
**structure-activity gradient**: potent Zn-chelating hydroxamates ~0.99 vs weak fatty-acid
valproate 0.91 vs DNMT inhibitors / IMiDs / steroid near 0. The screen recovers the right
pharmacological class at scale.
**Honest false negative:** romidepsin (potent HDAC inhibitor) ranked low (0.43) — it is a cyclic
depsipeptide PRODRUG (must be reduced to expose its Zn-binding thiol), which co-folding doesn't
model. The screen mishandles non-standard chemotypes (prodrugs, macrocycles).
The screening pipeline is validated. Next: run the full set (incl. the 240 random + negatives) to
hunt for NON-obvious HDAC2 binders (the actual discovery run), ~$15-20.
## Next steps
- [ ] Full screen (300 drugs) vs HDAC2 — discovery run for non-obvious binders.
- [ ] Investigate PKR: allosteric site may need the full assembly / better pocket definition.
- [ ] Phase 2 screen: rank the ~300-drug set against HDAC2 (the validated target) by P(binder);
positive-control recovery test at screen scale.