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

Abstract

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.

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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.

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