In silico drug discovery of SIRT2 inhibitors from natural source as anticancer agents

Abstract Sirtuin 2 (SIRT2) is a member of the sirtuin protein family, which includes lysine deacylases that are NAD+-dependent and organize several biological processes. Different forms of cancer have been associated with dysregulation of SIRT2 activity. Hence, identifying potent inhibitors for SIRT2 has piqued considerable attention in the drug discovery community. In the current study, the Natural Products Atlas (NPAtlas) database was mined to hunt potential SIRT2 inhibitors utilizing in silico techniques. Initially, the performance of the employed docking protocol to anticipate ligand-SIRT2 binding mode was assessed according to the accessible experimental data. Based on the predicted docking scores, the most promising NPAtlas molecules were selected and submitted to molecular dynamics (MD) simulations, followed by binding energy computations. Based on the MM-GBSA binding energy estimations over a 200 ns MD course, three NPAtlas compounds, namely NPA009578, NPA006805, and NPA001884, were identified with better ΔG binding towards SIRT2 protein than the native ligand (SirReal2) with values of − 59.9, − 57.4, − 53.5, and − 49.7 kcal/mol, respectively. On the basis of structural and energetic assessments, the identified NPAtlas compounds were confirmed to be steady over a 200 ns MD course. The drug-likeness and pharmacokinetic characteristics of the identified NPAtlas molecules were anticipated, and robust bioavailability was predicted. Conclusively, the current results propose potent inhibitors for SIRT2 deserving more in vitro/in vivo investigation.