Molecular dynamics articulated multilevel virtual screening protocol to discover novel dual PPAR α/γ agonists for anti-diabetic and metabolic applications

PPARα and PPARγ are isoforms of the nuclear receptor superfamily which regulate glucose and lipid metabolism. Activation of PPARα and PPARγ receptors by exogenous ligands could transactivate the expression of PPARα and PPARγ-dependent genes, and thereby, metabolic pathways get triggered, which are helpful to ameliorate treatment for the type 2 diabetes mellitus, and related metabolic complications. Herein, by understanding the structural requirements for ligands to activate PPARα and PPARγ proteins, we developed a multilevel in silico-based virtual screening protocol to identify novel chemical scaffolds and further design and synthesize two distinct series of glitazone derivatives with advantages over the classical PPARα and PPARγ agonists. Moreover, the synthesized compounds were biologically evaluated for PPARα and PPARγ transactivation potency from nuclear extracts of 3T3-L1 cell. Furthermore, glucose uptake assay on L6 cells confirmed the potency of the synthesized compounds toward glucose regulation. Percentage lipid-lowering potency was also assessed through triglyceride estimate from 3T3-L1 cell extracts. Results suggested the ligand binding mode was in orthosteric fashion as similar to classical agonists. Thus molecular docking and molecular dynamics (MD) simulation experiments were executed to validate our hypothesis on mode of ligands binding and protein complex stability. Altogether, the present study developed a newer protocol for virtual screening and enables to design of novel glitazones for activation of PPARα and PPARγ-mediated pathways. Accordingly, present approach will offer benefit as a therapeutic strategy against type 2 diabetes mellitus and associated metabolic complications. Graphical abstract