Interaction between peroxisome proliferator-activated receptors (PPARs)and their ligands investigated by molecular docking methods

Abstract

Peroxisome Proliferator-activated Receptors (PPARs) are transcription factors that play a major role in glucose and lipid metabolism. As other proteins from the nuclear receptor superfamily, the transcription activity of PPARs is regulated by the binding of endogenous or synthetic ligands, being attractive targets for development of antidiabetic and/or antilipidemic drugs. Recent studies have shown that partial agonists of PPARg, while displaying antidiabetic activity, do not display the concerning weight gain side effects characteristic of full agonists. Also growing in importance are ligands that can prevent phosphorylation of PPARg by Cdk5, since this post translational modification enhances the expression of genes associated to insulin resistance and adipogenesis. Moreover, the recent discovery that PPARg huge binding pocket can simultaneously accommodate up to three ligands adds complexity to the problem.Here we propose to apply state-of-art molecular docking methods to investigate the interaction between PPARs and their ligands. By docking several different ligands into PPARs binding cavity and analyzing docking results (binding poses and affinity), we expect to obtain insights on i) the molecular basis that make each ligand to behave as full agonist, partial agonist, antagonist, and/or phosphorylation inhibitor of PPARg; ii) the existence of response-specific 'sub-pockets' within the major binding cavity of PPARg; and ii) the molecular basis that make some ligands to display specificity towards different PPAR subtypes. Elucidation of these aspects will be of paramount importance for development of more efficient and specific drugs.This work will be performed with molecular docking methods developed by Prof. Abagyan, during a 6 month research exchange at his laboratory, at University of California, San Diego. Apart from extending the goals of my current PhD research project, this is an excellent opportunity to work and learn with a renowned group in the field of molecular docking. (AU)