Background: Human SIRT1 is a class III histone deacetylase (HDAC) family protein. As the overexpression of hSIRT1 leads to cancer, inhibiting its HDAC function may be a better strategy for the treatment of cancer. Till now, only a few reported inhibitor compounds have reached the stage of animal studies; hence, identifying high efficacy inhibitors of hSIRT1 is essential. Objective: The main objective of the study is to obtain a new class of inhibitor compounds of hSIRT1 by the rational structure-based method. Methodology: We performed virtual screening using AutoDock Vina for the HDAC domain of hSIRT1 against the Drug- Bank library containing 1,716 compounds. The recently determined crystal structure of the HDAC domain of hSIRT1 (PDB Id: 4KXQ) was used for docking studies. Subsequently, we performed molecular dynamics simulations and an invitro deacetylase assay for selected compounds. Results: Virtual screening studies yielded seven compounds from two chemical classes, namely diphenyl and oxycoumarin derivatives. Molecular dynamic simulations confirmed that the predicted seven compounds bind well to their respective complex structures. Moreover, four commercially available drugs containing the predicted compounds showed significant inhibition of hSIRT1 deacetylase activity in comparison to the known hSIRT1 inhibitor (sirtinol). Conclusion: Our results indicate that the compounds of the diphenyl and oxycoumarin series may serve as useful scaffolds in the development of new chemical libraries of hSIRT1 inhibitory activity.
