Structure-based drug design of small molecule SIRT1 modulators to treat cancer and metabolic disorders

• Crystal structure 4I5I (catalytic site) and AROS binding site (114–217 amino acids) were explored for designing inhibitors and activators of SIRT1, respectively.
• Virtual screening of Asinex database was performed and compounds showing good docking score and interactions were procured.
• Inhibitors showing good SIRT1 enzymatic inhibition were further evaluated for GI50 on four different cancer cell lines.
• Activators showing good SIRT1 activation were further studied for their effect on adipogenesis on 3T3-L1 cell line.
• Cell cycle analysis was done for the most potent inhibitors I4 and I5.

Sirtuins comprise a family of deacetylase enzymes that catalyze the removal of an acetyl moiety from the ɛ-amino group of lysine residues within protein targets. Sirtuin 1(SIRT1), a NAD+ dependent class III histone deacetylase is involved in a variety of human disorders such as obesity, type II diabetes, cancer and aging. Inhibition of SIRT1 could be useful for cancer treatment while activators can be useful for longevity and treating metabolic disorders. Hence we undertook an effort to design both inhibitors and activators using structure-based drug design techniques and report here the biological proof of concept. In this paper, we report diverse small molecule inhibitors with a potential to attenuate cancer growth designed based on high-throughput virtual screening and docking using the crystal structure of SIRT1. And small molecule activators with potential to suppress adipogenesis differentiation indicating their usefulness in obesity control was designed based on a homology model of SIRT1 activator domain.

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