IF an orally administered allosteric small-molecule CD38 inhibitor — designed de novo by targeting a cryptic pocket identified in AF-P28907-F1 through MD-ensemble conformational sampling (analogous to the SIRT3 allosteric discovery pipeline), featuring an indolyltriazine-derived scaffold (informed by privileged-scaffold precedent across NAD+-metabolism enzymes), and engineered to stabilize a catalytically inactive "loop-closed/Trp-locked" CD38 conformation analogous to the DFG-out mechanism in kinases — is administered orally at 10–30 mg/kg/day to aged (22–24 month) C57BL/6J male and female mice for 8 weeks following a prior 4-week senolytic course (dasatinib + quercetin, D+Q), thereby acting post-senolytics on residual SASP-induced, macrophage/stromal-expressed CD38,

THEN tissue NAD+ levels in liver, skeletal muscle, and kidney will be restored toward young-animal reference values (estimated +40–70% increase over vehicle-aged controls, measured by LC-MS/MS NAD+ quantification), CD38 NADase enzymatic activity in tissue lysates will be suppressed with apparent IC50 <100 nM in a fluorometric NAD+ consumption assay in human primary fibroblasts, selectivity over CD157 will exceed 50-fold, and the compound will achieve Caco-2 permeability >5×10⁻⁶ cm/s and human liver microsomal t½ >60 min,

BECAUSE the following causal chain operates:

1. Senescent cell-secreted SASP factors — not senescent cells themselves — are the dominant paracrine inducers of CD38 expression in neighboring macrophages and stromal cells, meaning senolytic clearance of senescent cells does not eliminate the elevated CD38 activity that has already been installed in the tissue microenvironment and that continues to degrade NAD+ in a feed-forward manner (SASP-driven CD38 induction demonstrated)[https://doi.org/10.1016/j.bbrc.2019.03.199].

2. CD38 is the primary NADase responsible for age-associated tissue NAD+ decline; genetic or pharmacological CD38 ablation — but not mere slowing of biosynthesis decline — is sufficient to restore (repair) NAD+ to young-animal levels and reverse downstream metabolic dysfunction, confirming this is a repair-capable target (CD38 inhibitor 78c reverses tissue NAD+ decline in aged mice)[https://doi.org/10.1016/j.cmet.2018.03.016].

3. Existing inhibitor 78c occupies the canonical NAD+/substrate binding site and achieves competitive inhibition; however, active-site inhibitors face displacement by the high intracellular NAD+ concentrations present during recovery, and no allosteric CD38 inhibitor has been described — creating a mechanistic gap that an allosteric stabilizer of the inactive conformation could uniquely fill [SPECULATIVE: gap assessment based on absence in evidence set; needs ChEMBL/PubChem confirmation].

4. The computational strategy of integrating AlphaFold structure prediction with MD-ensemble generation, mechanism-based kinetic modeling, and large-scale virtual screening has been experimentally validated for identifying al...

SENS category: LysoSENS

Key references: • doi.org/10.1016/j.bbrc.2019.03.199]. • doi.org/10.1016/j.cmet.2018.03.016]. • doi.org/10.1101/2023.11.09.566481]. • doi.org/10.1101/2024.05.23.595569]. • doi.org/10.1101/2025.04.14.648780].