Identification of Selisistat Derivatives as SIRT1-3 Inhibitors by in Silico Virtual Screening

Sirtuins family are a Nicotinamide Adenine Dinucleotide (NAD+) dependent histone deacetylase enzyme. have been implicated in the pathogenesis of various diseases including cancer, neurological disorders and metabolic syndromes, hence sirtuins appointed as promising therapeutic target for diseases, by regulating its activity small molecules modulators. The indole containing selisistat (EX-527) derivatives set most potent selective SIRT1 inhibitors. Selisistat showed an effective sirtuin inhibition on cancer cell line, has reached clinical trials endometriosis Huntington’s disease. In this study were designed virtually studied means molecular docking, ADMET, dynamics (MD) simulations. Two virtual binding affinity SIRT1-3 proteins. Compound 1 exhibits stronger silico SIRT2 affinities than EX-527, whereas compound 8 prefers SIRT3 binding. ADMET analysis active demonstrated acceptable drug-like profile desirable pharmacokinetics properties. MD simulation revealed that had significantly better alignment with proteins EX-527 according to Root Mean Square Deviation (RMSD) Fluctuation (RMSF) data, while perfect fitting protein EX-527.