{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:24:32Z","timestamp":1785439472560,"version":"3.56.0"},"reference-count":68,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology of China Fund","award":["2021YFA1100800"],"award-info":[{"award-number":["2021YFA1100800"]}]},{"name":"Jiangsu Basic Research Center for Synthetic Biology","award":["BK20233003"],"award-info":[{"award-number":["BK20233003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>CD38 is a multifunctional enzyme that plays a pivotal role in NAD+ metabolism and calcium signaling, and its abnormal activity is closely associated with multiple myeloma, age-related metabolic decline, neurodegenerative diseases, and other disorders. Although monoclonal antibodies such as daratumumab have been approved for clinical application, their inherent limitations necessitate the development of novel small-molecule CD38 inhibitors. In this study, we employed DNA-encoded library (DEL) technology for the high-throughput screening of CD38 inhibitors, using a DEL library containing more than 100,000 unique compounds to screen against recombinant human CD38. A total of 1043 enriched compounds were initially identified, and after rigorous validation and screening to exclude non-specific binding and previously reported active compounds, eight hit compounds with diverse chemical scaffolds were obtained, among which Fenbendazole\u2014a clinically approved antiparasitic drug\u2014was included. Surface plasmon resonance (SPR) assays confirmed the direct binding of these hit compounds to CD38, with dissociation constants (KD) ranging from 7.74 \u00d7 10\u22125 M to 2.15 \u00d7 10\u22124 M. Fluorescence-based enzymatic activity assays demonstrated that these compounds exert dose-dependent inhibitory effects on both the hydrolase (with \u03b5-NAD as substrate) and cyclase (with NGD as substrate) activities of CD38. Further structure\u2013activity relationship (SAR) analysis of Fenbendazole analogues revealed the critical structural features that regulate CD38 inhibitory potency, and Flubendazole was found to exhibit excellent inhibitory activity, with an IC50 of 14.78 \u00b1 4.21 \u03bcM against CD38 hydrolase and 26.31 \u00b1 3.40 \u03bcM against cyclase. Molecular docking and 100 ns molecular dynamics (MD) simulations further elucidated the molecular mechanism of CD38 inhibition by lead compounds, confirming that van der Waals interactions are the main driving force for the binding of small-molecule ligands to CD38, with conserved aromatic residues in the active site mediating ligand recognition. This study validates DEL technology as an efficient and reliable platform for the discovery of CD38 inhibitors, and the identified lead compounds\u2014especially Fenbendazole and its analog Flubendazole\u2014provide valuable molecular scaffolds for the further structural optimization of CD38 inhibitors. These findings lay a solid foundation for the development of novel therapeutic agents for the treatment of CD38-associated diseases.<\/jats:p>","DOI":"10.3390\/molecules31050864","type":"journal-article","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T13:11:22Z","timestamp":1772716282000},"page":"864","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Rapid Discovery of CD38 Inhibitor via DNA-Encoded Natural Product Library Screening"],"prefix":"10.3390","volume":"31","author":[{"given":"Xinyu","family":"Shi","sequence":"first","affiliation":[{"name":"State Key Laboratory of Microbial Technology, School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze","family":"Liang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Technology, School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Meng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Technology, School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Technology, School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China"},{"name":"Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1775-5533","authenticated-orcid":false,"given":"Lei","family":"Yan","sequence":"additional","affiliation":[{"name":"Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 200120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1021\/ja808387g","article-title":"Mechanism-Based Small Molecule Probes for Labeling CD38 on Live Cells","volume":"131","author":"Jiang","year":"2009","journal-title":"J. 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