Supplementary file 1_Elucidating binding hot spots and structural stability in sirtuin family proteins for selective inhibitors: a computational approach.docx

BackgroundThe sirtuin (SIRT) family is an NAD+-dependent class III histone deacetylase protein that comprises seven members (SIRT1–7). SIRTs are involved in many cellular pathways, which enable them to act as significant regulators of critical diseases such as cancer, cardiovascular disease, respiratory disease, and diabetes. Despite extensive research conducted to understand SIRT biology, many areas remain unexplored, such as the lack of SIRT isoform selectivity and specificity, restrained potency, limited bioavailability, poor pharmacokinetic and pharmacodynamic properties, and insufficient clinical and preclinical trials. Our study focused on one of the major research gaps, i.e., “lack of SIRT isoform selectivity and specificity,” through extensive computational exploration.
MethodsThe workflow of our study included molecular docking and molecular dynamics studies to deeply explore conformational dynamics and binding hot spots selective to each SIRT isoform.
ResultsAs an outcome of our study, we predicted the major flexible regions in each isoform, which may turn out to be selective for each SIRT isoform. Additionally, we predicted SIRT isoform-selective key residues that may regulate the inhibitory potential of SIRT proteins. The primary SIRT isoform-selective residues for SIRT1 were Phe273, Phe297, Tyr280, and His363; for SIRT2, they were Phe119, His187, Val233, Phe235, and Leu239; for SIRT3, they were Leu248, Glu296, and Arg301; for SIRT5, they were Phe70, Tyr102, Gln140, and His158; and for SIRT6, they were Asp61, Trp69, His131, Trp186, Ser214, Arg218, and Leu239.
ConclusionIn this study, we provided a deep cognizance of SIRT biology and a fruitful initiative for in vitro exploration of SIRT-selective inhibitors and an in silico contribution toward their clinical trial success.