5-Benzylidene-hydantoin is a new scaffold for SIRT inhibition: From virtual screening to activity assays

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Lionel SacconnayAlessandra Nurisso

Abstract

Sirtuins (SIRTs) are a family of enzymes able to catalyze the deacetylation of the N-acetyl lysines of both histone and non-histone substrates. Inhibition of SIRTs catalytic activity was recently reported in the literature as being beneficial in human diseases, with very promising applications in cancer therapy and enzymatic neurodegeneration. By combining a structure-based virtual screening of the Specs database with cell-based assays, we identified the 5-benzylidene-hydantoin as new scaffold for the inhibition of SIRT2 catalytic activity. Compound 97 (Specs ID AH-487/41657829), active in the low μM range against SIRT2, showed the optimal physicochemical properties for passive absorption as well as relatively low cytotoxicity in vitro. Further studies revealed non-competitive and mixed-type kinetics toward acetyl-lysine substrates and NAD(+), respectively, and a non-selective profile for SIRT inhibition. A binding mode consistent with the experimental evidence was proposed by molecular modeling. Additionally, the levels of acetyl-p53 were shown to be increased in HeLa cells treated with 97. Taken together, these results encourage further investigation of 5-benzylidene-hydantoin derivatives for their SIRT-related therapeutic ef...Continue Reading

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Citations

Mar 17, 2017·Journal of Chemical Information and Modeling·Shenzhen HuangShengyong Yang
Feb 15, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Berin KaramanFidele Ntie-Kang
Apr 13, 2018·Future Medicinal Chemistry·Ziyan ZhouXiaoming Zha
Jan 10, 2019·European Journal of Medicinal Chemistry·SeoHyun ChoDongyun Shin

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