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

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>

docs/results/screen_HDAC2_pilot.csv

@@ -0,0 +1,25 @@
+rank,drug,P_binder,affinity,inclusion_reason
+1,trichostatin-a,0.9994845986366272,-2.883908271789551,related_mechanism
+2,vorinostat,0.9994641542434692,-1.7357702255249023,related_mechanism
+3,panobinostat,0.9983962774276733,-2.4892501831054688,related_mechanism
+4,belinostat,0.9970909357070923,-2.102327823638916,related_mechanism
+5,scriptaid,0.9957252740859985,-1.5838574171066284,related_mechanism
+6,mocetinostat,0.9910210371017456,-1.3829972743988037,related_mechanism
+7,entinostat,0.9903219938278198,-0.6888977289199829,related_mechanism
+8,apicidin,0.9882931113243103,-2.2579169273376465,related_mechanism
+9,valproic-acid,0.9134805202484131,0.3317195773124695,related_mechanism
+10,hydroxyurea,0.77649986743927,1.2352395057678223,ground_truth
+11,curcumin,0.6803375482559204,0.9697343707084656,related_mechanism
+12,sulforaphane,0.5829939842224121,0.6017141342163086,related_mechanism
+13,resveratrol,0.5800595283508301,1.1647570133209229,related_mechanism
+14,tadalafil,0.5426475405693054,0.21663367748260498,related_mechanism
+15,glutamine,0.4674023389816284,2.029467821121216,ground_truth
+16,quercetin,0.45189985632896423,0.34488344192504883,related_mechanism
+17,romidepsin,0.4316568374633789,-0.8200547099113464,related_mechanism
+18,decitabine,0.38500306010246277,0.8381982445716858,related_mechanism
+19,azacitidine,0.31987687945365906,0.6874549388885498,related_mechanism
+20,sildenafil,0.15390564501285553,0.26623794436454773,related_mechanism
+21,thalidomide,0.1190553605556488,1.9194087982177734,related_mechanism
+22,pomalidomide,0.11849743872880936,1.7003729343414307,related_mechanism
+23,lenalidomide,0.09446469694375992,1.9872398376464844,related_mechanism
+24,dexamethasone,0.031893711537122726,0.5724264979362488,related_mechanism

docs/structure_binding_notes.md

@@ -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.