Pharmacoinformatic Studies on 4-Thiazolyl-phenoxy Tail Containing Indanyl Acetic Acid Derivatives as PPAR-Pan Agonists as Potent Anti-Diabetic Agent

Abstract:

Aim: The increasing incidences of type 2 diabetes mellitus, represents a considerable public health problem and characterized by loss in sensitivity of tissues to insulin which can be restored by activation of Peroxisome Proliferator-Activated Receptors (PPARs). The present work takes in consideration for the development of PPAR agonists, which can activate PPARs and is expected to lower LDL cholesterol and triglycerides, raise HDL cholesterol and normalize hyperglycaemia. Materials and Methods: Quantitative Structure-Activity Relationship (QSAR) study is performed by means of Multiple Linear Regression (MLR) analysis on a set of indanyl acetic acid derivatives followed by ADMET prediction and Docking Studies. Results: A good correlation is found by regression analysis between the observed and predicted activities as evident by their R² (0.81), Q2 (0.81) and R² pred (0.86) for PPARα and R² (0.66), Q2 (0.66) and R² pred (0.90) for PPARδ and R² (0.82), Q2 (0.77) and R² pred (0.58) for PPARγ respectively. Molecular docking of the ligands qualifying all the Drug Likeness properties to the proteins PPARα (PDB ID: 3ET1), PPARδ (PDB ID: 3ET2) and PPARγ (PDB ID: 3ET3) with FlexX score -11.98, -9.69 and -21.48 respectively followed by core hoping. Conclusion: Docking studies revealed that hydrogen-bonding interactions are crucial for the binding of ligands with the target. Core replacement of the best-docked conformations of the selected ligand is performed in order to obtain more potent and novel ligands.

Key words: Quantitative structure-activity relationship, Multiple Linear Regression, Molecular docking, Drug Likeness, Hydrogen-bonding interaction.