Deciphering the structural attributes of PPAR-γ and SIRT1 to identify their dual activators using a combined...

PPAR-γ and SIRT1 are the emerging targets that are vital in diabetes and diabetic complications. So, the development of dual activators for PPAR-γ and SIRT1 can be a good strategy in the treatment of diabetes and diabetic complications and in order to reduce the adverse effects that occur from the activation of these targets. The network analysis was applied to study the protein-protein interactions. Similarity-based virtual screening was done to screen Fisetin-based molecules, and docking analysis was performed for both targets. In addition, an ADME study and electrostatic complementarity analysis were conducted to study the role of binding energies between the ligands and the targets. The Molecular Dynamics (MD) simulation was performed to study the stable binding conformation. Different validation metrics from MD analysis, such as RMSD, RMSF, R_g, PCA and free energy landscape (FEL), were analysed to evaluate the stability of the compounds with the target proteins. Moreover, the WaterSwap and MMPBSA analyses were also done to calculate the binding free energy of the compounds. The findings from this extensive evaluation depicted that the selected three molecules can be used as potent and safe dual activators of PPAR-γ and SIRT1 to combat diabetes and several diabetic complications.