De novo Based Ligand generation and Docking studies of PPARδ Agonists: Correlations between Predicted Biological activity vs. Biopharmaceutical Descriptors

Abstract

Molecular docking was performed on a series of bisaryl substituted thiazoles and oxazoles as PPARδ agonists. The docking technique was applied to dock a set of representative compounds within the active site region of 3D5F using Molegro Virtual Docker v 4.0.0. For these compounds, the correlation between binding free energy (kcal/mol) and log (1/EC50) values produces a good correlation coefficient (r2 = 0.719). The docking simulation clearly predicted the binding mode that is nearly similar to the crystallographic binding mode within 0.91A RMSD. Based on the validations and interactions made by Ar1 and Ar2 substituents, ligand design was initiated considering simple combinations. For the designed compounds biopharmaceutical properties e.g. Lipophilicity (logP), Solubility (logS), Ionization constant (pKa), Distribution coefficient (logD) are predicted computationally using ACD/ChemSketch v 12.0. The hydrogen bond interactions are examined and bivariate statistical correlation between predicted biological activity (log (1/EC50) and biopharmaceutical properties are considered for evaluation. Ligand 11 (cC) thus, showed high binding energy (-206.73 kcal/mol) against PPARδ. The results avail to understand the type of interactions that occur between designed ligands with PPARδ binding site region and explain the importance of Ar1 and Ar2 substitutions on derivatives of bisaryl substituted thiazoles and oxazoles.