Flavonoids as Modulators of Sirtuin-6 for Management of Metabolic Syndrome: An In - Silico Approach

Abstract

Sirtuin 6 (SIRT6), a member of the sirtuin family, regulates various cellular processes involved in aging, metabolism, and cancer. Dysregulation of SIRT6 is widely observed in metabolic syndrome (MS), and some reported chemical activators of SIRT6 have shown therapeutic success. There is a need to further explore natural compounds with SIRT6 activator activity that are affordable and have fewer side effects. The aim of this study was to identify novel compounds targeting SIRT6, providing a new approach in developing therapy for MS. A library of 239 flavonoid compounds was docked against SIRT6 (PDB ID-3ZG6) using the Glide module of Schrödinger. Based on docking scores, the top 12 flavonoid compounds with promising binding affinities (docking score <-10.26) were identified and were then subjected to ADMET profiling using SwissADME and pkCSM. ADMET profiling demonstrated that two flavonoid compounds i.e., Isosilybin and Tilianin possessed excellent drug-like molecules, suggesting their potential as allosteric SIRT6 activators. The interactions of these compounds were further validated by MM-GBSA and molecular dynamics (MD) using Prime and Desmond of the Schrödinger Suite respectively. MM-GBSA and MD revealed that both the selected flavonoid compounds exhibited strong protein-ligand interactions, indicating their potential as SIRT6 activators. This study provides potential evidence for the effectiveness of these flavonoid compounds as potent SIRT6 activators.