Molecular recognition of a series of oxadiazole-substituted α-isopropoxy phenylpropanoic acids by PPARα and PPARγ was investigated by using molecular modeling and 3D-QSAR analyses. The binding models of these compounds were determined by hydrophobic property analyses and molecular docking procedure FlexX. It was found that the hydrophilic heads of these compounds form four specific conserved hydrogen bonds with the ligand binding pockets of PPARα and PPARγ, which results in fixed head conformations. On the contrary, their hydrophobic tails adopt different configurations to make contacts with hydrophobic region. The oxadiazole-ring-related hydrogen bond interactions well elucidate the structural features governing the different binding behavior of these agonists against PPARα and PPARγ. Based on these active conformations, highly predictive comparative molecular similarity indices analysis (CoMSIA) models were derived, which not only is consistent with the experimental results but also could be mapped back to the receptor topology and the ligand-receptor interaction models. The simulation results reveal the structure-activity relationship of these compounds at the molecular level and provide new insights for the design of novel potent PPARα and PPARγ dual agonists.
Keywords: Molecular Modeling, oxadiazole, PPARα, PPARγ, 3D-QSAR analyses, structure-activity relationship, ligand-receptor