CD38 (UniProt P28907) is a bifunctional NAD hydrolase/cyclase and dominant NAD-consumer in aged tissues. Inhibition raises NAD+ levels and extends healthspan in mouse models. This tick resolves PDB 2I65 (the literature-canonical NAD-bound co-crystal) and performs geometric hotspot profiling on chain A residues T102, C119, D155, D156, L157, D179, S181, Q226 at 4.5 Å neighbor radius. Ki affinity data for P28907 are queried from BindingDB to establish a reference inhibitor baseline. PubMed search targets mutagenesis / selectivity literature to annotate each hotspot residue with functional importance scores. Outputs will anchor the BindCraft conditioning hotspot list and define the kill criterion (>2 Å deviation from 2I65 geometry triggers pocket-ensemble fallback). Next tick: (1) cross-reference hotspot geometry from 2I65 vs 4F45 to confirm pocket ensemble consistency; (2) draft BindCraft recipe conditioned on confirmed hotspot set; (3) create protein_design stub for first binder candidate.
Details
- disease
- aging, nad+ depletion, metabolic decline, neurodegeneration
- target_ref
- UniProt:P28907 / PDB:2I65 / PDB:4F45
- primary_endpoint
- Hotspot table covers all 8 profiled residues with at least one literature-backed score dimension (mutagenesis or conservation) per residue
- identification_strategy
- in_silico_KO
Raw fields (3)
- assay_spec
Planned: geometric hotspot profile from PDB 2I65 chain A (residues T102, C119, D155, D156, L157, D179, S181, Q226, 4.5 Å neighbor radius). Success criterion: all 8 residues resolved with neighbor count ≥2 and centroid coordinates returned. Mutagenesis literature will annotate each residue with functional-loss evidence. Ki reference inhibitors from BindingDB will set the competitive-binding performance bar for designed binders (target: predicted ipTM > 0.7, AF2-refolded pLDDT > 80, predicted Ki < 100 nM).
- hypothesis
A de novo protein binder conditioned on the CD38 catalytic cleft hotspot residues (T102, C119, D155, D156, L157, D179, S181, Q226 from PDB 2I65 chain A) will competitively inhibit CD38 NAD+ hydrolase activity with predicted ipTM > 0.7 and AF2-Multimer pLDDT > 80, outperforming small-molecule reference inhibitors (apigenin, quercetin IC50 ~ 10-100 µM range) on in-silico binding geometry metrics, thereby providing a scaffold for restoring NAD+ levels in aged tissues.
- kill_criteria
Abort or revise if: 2GVJ pocket conformation may differ from 2I65 — if geometry diverges >2 Å on catalytic residues, flag for separate pocket-ensemble run; Mutagenesis data may be sparse in literature; fall back to ConSurf conservation scores from UniProt P28907 alignment if needed; BindCraft config stub is planned output only — do not report binding metrics until BindCraft actually runs