Structural exploration of PPARγ modulators through pharmacophore mapping, fragment-based design, docking, and molecular dynamics simulation analyses

Abstract

Peroxisome proliferator-activated gamma receptor is an attractive therapeutic target involving various types of metabolic syndrome. Viewing the importance of peroxisome proliferator-activated gamma receptor modulators, ligand and energetically optimized pharmacophores (e-pharmacophore), hologram-based quantitative structural activity relationships, and classification-based Bayesian models were developed, followed by molecular docking, mechanics, and dynamic analyses to search for essential structural requirements in the molecules for potent and selective peroxisome proliferator-activated gamma receptor modulation. Both ligand and e-pharmacophore models suggest that aromatic ring feature plays the crucial role, whereas the hologram-based quantitative structural activity relationships study indicates that phenyl and indole aromatic rings are essential scafolds for imparting selective peroxisome proliferator-activated gamma receptor modulation. Further, the e-pharmacophore model, molecular docking, and dynamics studies depict the importance of a carboxyl group for modulating peroxisome proliferator-activated gamma receptor agonistic activity through generating strong H-bonds with the active amino acid residues (His323, Tyr327, His449, and Tyr473, etc). The multi chemometrics modeling studies provide some insight into the prime structural features responsible for significant agonistic property of peroxisome proliferator-activated gamma receptor ligands.