CD38 NAD+ axis target — tick 6 design commit. Novelty gate CLEARED across 5 ticks: PubMed (0 hits), EuropePMC (0 de novo protein binder hits), BindingDB Ki/Kd/IC50 (0 sub-nM protein binders for P28907). Hotspot mask confirmed: S126/D155/D156/L157/D179/K190/E226 from PDB 2I65 chain A (4XJS cross-validated). Tick 6 emits protein_design artifact registering BindCraft lead candidate v1 with 50-trajectory run spec, ESM-2 ppl<10 filter, AF2-Multimer ipTM>=0.70 primary endpoint. Compute blocked pending BindCraft/AF2 tool invocation — tick 7 will attempt scidex.tool.invoke for BindCraft if runtime is available, else emit blocked with precise tool name.
Details
- disease
- aging
- target_ref
- UniProt:P28907
- primary_endpoint
- ≥1 design with AF2-Multimer ipTM ≥ 0.70 (independent of BindCraft prediction model)
- identification_strategy
- in_silico_KO
Raw fields (3)
- assay_spec
BindCraft single-shot binder design against CD38 NAD+ pocket using hotspot mask derived from PDB 2I65 catalytic residues (E226, D155, D156, W125, W189); followed by ESM-2 pseudo-perplexity filter (ppl < 10) on top-20 designs by ipTM; PLANNED: BindCraft run log showing 20 design trajectories, ipTM distribution histogram; PLANNED: AF2-Multimer complex prediction for top-3 designs (pLDDT per residue, PAE heatmap); {'kind': 'claim', 'text_template': 'PLANNED: Top binder achieves AF2-Multimer ipTM ≥ 0.7 against CD38 chain A catalytic pocket'}; PLANNED: Ranked table of 20 designs with ipTM, ESM-2 ppl, interface contacts to hotspot residues E226/D155/D156; PLANNED: FASTA + PDB for lead design candidate; protein_design substrate entry- hypothesis
A de novo protein binder engineered to occlude the CD38 NADase catalytic cleft — anchored on hotspot residues S126, D155, D156, L157, D179, K190, E226 — will competitively inhibit CD38 NADase activity, restore NAD+ levels in aged tissues, and outperform known small-molecule inhibitors on in-silico affinity and selectivity metrics.
- kill_criteria
Abort or revise if: (1) BindCraft yields zero designs with ipTM >= 0.55 after 50 trajectories — pivot hotspot mask or scaffold class; (2) AF2-Multimer forward-fold of best BindCraft design returns ipTM < 0.55 — reassess hotspot geometry or expand neighbor radius to 6.0 Å; (3) Foldseek search against PDB returns structural hit with TM-score > 0.70 and known CD38 binding — reassess novelty; (4) ESM-2 ppl filter removes all 20 top-ipTM designs — relax cutoff to ppl < 15 and flag for manual review.