Tetrameric Stilbenoids from Shorea macrophylla as Potential Modulators of Sirtuin ۶: A Molecular Docking and Molecular Dynamics Study

Natural products remain a rich source of structurally diverse scaffolds for drug discovery, particularly for targets involved in aging and metabolic regulation, such as Sirtuin ۶ (Sirt۶). Two tetrameric stilbenoids, hopeaphenol (۱), and isohopeaphenol (۲), were isolated from the methanolic extract of Shorea macrophylla roots via phytochemical analysis. Their structures were then elucidated using UV-Vis, ۱D, and ۲D NMR spectroscopy. Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding free-energy calculations were subsequently performed to evaluate their potential as Sirt۶ modulators. Hopeaphenol (۱) exhibited a more favorable docking score (−۵۷.۲۱ kcal/mol) than the reference ligand Xeg (−۴۸.۷۱ kcal/mol) and isohopeaphenol (۲) (−۴۸.۲۱ kcal/mol). MD simulations indicated stable protein-ligand complexes, with both stilbenoids remaining consistently accommodated within the binding pocket without perturbing protein structure. Binding free-energy calculations further supported a stronger affinity for hopeaphenol (۱) (ΔGbind = −۴۴.۹۷ ± ۰.۱۷ kcal/mol). Per-residue energy decomposition identified key stabilizing interactions with hydrophobic and aromatic residues V۶۱, F۷۷, H۱۲۴, W۱۷۹, and M۱۴۸, underscoring the importance of dispersion-driven contacts in ligand recognition. Overall, these findings provide molecular insight into oligomeric stilbenoid interactions with Sirt۶ and highlight hopeaphenol (۱) as a promising scaffold for Sirt۶ modulation, warranting further experimental validation in relevant biological models.

کلیدواژه ها:

Shorea macrophylla ، Sirtuin ۶ ، Stilbenoids ، Molecular dynamics simulations ، Hopeaphenol ، Isohopeaphenol