Chemometric Modelling of PPAR-α and PPAR-γ Dual Agonists for the Treatment of Type-2 Diabetes

Type-2 diabetes mellitus (T2DM) is an enervating and fast-growing disease characterized by hyperglycaemia. The increasing incidences of T2DM represent a public health problem. The disease is characterized by loss in sensitivity of tissues towards insulin, which can be restored by the activation of peroxisome proliferatoractivated receptors (PPARs). PPARs are members of the nuclear receptor family, which function as a ligand-dependent transcription factor. The aim of the present work is to develop ligands, which can activate PPARs and are expected to lower LDL cholesterol and triglycerides, raise HDL cholesterol, and normalize hyperglycaemia. Here quantitative structure-activity relationship (QSAR) study is performed, followed by pharmacophore modelling and docking of the most active compound to the proteins PPAR-γ (PDB ID: 1FM9) and PPAR-α (PDB ID : 1K7L). Docking studies revealed the importance of hydrogen-bonding interactions for the binding of targets with the ligand. QSAR study is performed on the dataset by means of multiple linear regression and partial least squares (PLS) techniques. A good correlation is found by regression analysis between the observed and predicted activities as evident by their R² (0.651), Q² (0.649) and R²_pred (0.606) for PPAR-γ, and R² (0.784), Q² (0.774) and R²_pred (0.841) for PPAR-α. Subsequent analysis of the model by PLS cross-validation technique yields a similar set of coefficients. Pharmacophore studies reveal the importance of features like hydrogen bond donor, hydrogen bond acceptor and aromaticity, which contribute significantly in both models and are essential for binding of ligands to the receptor and also for their proper functioning.