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

Sirtuin 6 (SIRT6), a member of the sirtuin family, regulates various cellular processes involved in aging, metabolism, and cancer. Dysregulation of SIRT6 has been widely observed in metabolic syndrome (MS), and some chemical activators of SIRT6 have shown therapeutic success. There is a need to 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 and provide a new approach for developing therapies for MS. A library of 239 flavonoid compounds was docked against SIRT6 (PDB ID-3ZG6) using the Schrödinger Glide Module. Based on docking scores, the top 12 flavonoid compounds with promising binding affinities (docking score <-10.26) were identified and subjected to ADMET profiling using SwissADME and pkCSM. ADMET profiling demonstrated that two flavonoid compounds, Isosilybin and Tilianin, possess excellent drug-like properties, suggesting their potential as allosteric SIRT6 activators. The interactions between these compounds were further validated by MM-GBSA and molecular dynamics (MD) using Prime and Desmond of the Schrödinger Suite. 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 evidence for the effectiveness of these flavonoid compounds as potent SIRT6 activators.