Chemical Biology and Drug Design
Chemical Biology and Drug Design
5 years ago

Structure-based discovery of new selective small molecule sirtuin 5 inhibitors

Structure-based discovery of new selective small molecule sirtuin 5 inhibitors
Li Jing, Wei-Jian Li, Zhu-Jun Yu, Qiang Chen, Guo-Bo Li, Ling-Ling Yang, Yong Wu, Hua-Li Wang, Sha Liu, Xu Cheng, Yamei Yu, Sen Ji
Human sirtuin 5 (SIRT5) is a protein deacylase regulating metabolic pathways and stress responses, and is implicated in metabolism-related diseases. Small molecule inhibitors for SIRT5 are sought as chemical tools and potential therapeutics. Herein we proposed a customized virtual screening approach targeting catalytically important and unique residues Tyr102 and Arg105 of SIRT5. Of the 20 tested virtual screening hits, 6 compounds displayed marked inhibitory activities against SIRT5. For the hit compound 19, a series of new synthesized (E)-2-cyano-N-phenyl-3-(5-phenylfuran-2-yl)acrylamide derivatives/analogues were carried out structure-activity relationship analyses, resulting in new more potent inhibitors, among which 37 displayed the most potent inhibition to SIRT5 with an IC50 value of 5.59 ± 0.75 μM. The biochemical studies revealed that 37 likely acts via competitive inhibition with the succinyl-lysine substrate, rather than the NAD+ cofactor, and it manifested substantial selectivity for SIRT5 over SIRT2 and SIRT6. This study will aid further efforts to develop new selective SIRT5 inhibitors as tools and therapeutics. This article is protected by copyright. All rights reserved. This study proposed a customized virtual screening approach targeting catalytically important and unique residues Tyr102 and Arg105 of SIRT5, which led to the identification of new hit compounds. Subsequent structure-activity relationship studies resulted in new more potent SIRT5 inhibitors. The biochemical studies revealed that the most potent compound 37 likely acts via competitive inhibition with the succinyl-lysine substrate, rather than the NAD+ cofactor, and it manifested substantial selectivity for SIRT5 over SIRT2 and SIRT6.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13077

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