Rapid Discovery of CD38 Inhibitor via DNA-Encoded Natural Product Library Screening - PubMed
4 hours ago
- #CD38-inhibitors
- #drug-discovery
- #DNA-encoded-libraries
- CD38 is a multifunctional enzyme linked to NAD+ metabolism, calcium signaling, and diseases like multiple myeloma and neurodegenerative disorders.
- DNA-encoded library (DEL) technology was used to screen over 100,000 compounds for CD38 inhibitors, identifying 1,043 enriched compounds.
- Eight hit compounds with diverse scaffolds were validated, including Fenbendazole, an antiparasitic drug, showing direct binding to CD38 via SPR assays.
- Fluorescence-based assays confirmed dose-dependent inhibition of CD38's hydrolase and cyclase activities by the hit compounds.
- SAR analysis highlighted critical structural features for CD38 inhibition, with Flubendazole showing strong inhibitory activity (IC50 ~14.78 μM for hydrolase).
- Molecular docking and dynamics simulations revealed van der Waals interactions and aromatic residues as key for ligand binding to CD38.
- The study validates DEL as an efficient platform for CD38 inhibitor discovery, with Fenbendazole and Flubendazole as promising scaffolds for optimization.