In-silico Analysis of Phenyl Propanoic Acid Derivatives to Design Potent Peroxisome Proliferator-activated Receptor (PPAR) Dual Agonists for Type 2 Diabetes mellitus Therapy

Abstract

Background: Type 2 Diabetes mellitus (T2DM) is an enfeeble and thriving disorder outlined by the hyperglycemia. The exponentially rising prevalence of T2DM, serves a major dilemma to public health and is marked by a fall in reactiveness of the tissues with respect to insulin that can be restored by the stimulation of Peroxisome Proliferator-Activated Receptors (PPARs). Identification of the structural features of ligands is performed in this study, which can help in modelling potent molecules to activate PPARs and normalize hyperglycaemia. Multiple Linear Regression (MLR) analysis was performed on the dataset of the PPAR's agonists followed by docking analysis and Molecular Dynamics Simulation (MDS). A 'sum-model' is developed to design PPAR activators by adding the activities (EC 50 ) of the ligands contrary to individual subtypes (PPARα and PPARγ) and using it as dependent parameter followed by validation using a test set of molecules, calculating the modified r 2 and 'Leave One-Out' (LOO) method. The sum-model represents the optimum statistical outcome with R 2 = 0.745 and R2pred = 0.838 while the corresponding values for the other two models are 0.747 and 0.732 for α-model, 0.600 and 0.677 for γ-model respectively. Docking analysis revealed that hydrogen bonding interactions are fundamental feature essential for the interaction among PPARs and Phenyl Propanoic Acid (PPA) derivatives. Docking of the most active compound to the proteins was followed by dynamically stabilizing the docked complexes of the PPARγ (1FM9) and PPARα (1K7L). The molecule PPARγ was found to stabilize at 2717ps having an RMSD value of 0.607nm while PPARα stabilized at 4500ps with an RMSD value of 1.1213 nm. The potential energy, kinetic energy and total energy of the 1FM9 at 2717ps were found to be -543611 kj/mol, 96167 kj/ mol and -441916 kj/mol, respectively, and that of 1K7L at 4500ps are found to be -2.995595 kj/mol, 542616 kj/mol and -2.45353 kj/mol respectively.