Structural characterization of the peroxisome proliferator-activated receptors (PPARs) types alpha and gamma complexes and its agonists

Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that control various functions in human organism and they play key roles in the control of glucose and lipid metabolism. There are three different PPAR isotypes: PPAR±, PPAR² e PPAR³. PPAR³ is a molecular target of TZD agonists, which are clinically used drugs in the control of type 2 diabetes by increasing insulin sensitivity. Whereas fibrates are drugs that act on PPAR± and are used to lower serum triglyceride levels. The most patients who have type 2 diabetes also display lipid metabolism disorders. Even with the existence of drugs that can control these metabolic disorders, the search of dual agonist for PPAR± and PPAR ³ is a major challenge in the control of metabolic syndrome, because this compound could combine both therapeutic effects in a single molecule. GL479 is a dual agonist that was synthesized based on a combination of two key pharmacophores, with the ability to bind in the both PPARs, ± and ³. Thus, this study reveals the structural basis for this dual agonist GL479 by structural determination of the complexes PPAR±-LBD:GL479 and PPAR³-LBD:GL479. The detailed analysis of these complexes showed different ligand binding modes for each receptor, however, in the both cases the GL479 interacted with the Tyr of H12. In the PPAR±-LBD structure the ligand acquired the features of full agonist and in the case of PPAR³-LBD, GL479 adopted features of a partial agonist dependent of H12 interaction. In addition to the dual agonist analysis, sixteen compounds were identified as PPAR³ ligand by docking. Three of these ligands were characterized by ThermoFluor and fluorescence polarization, which resulted in IC50 values smaller than 10 ¼M. Additionally, one of the compounds, identified by docking, was co-crystallized with PPAR³. The ligand conformation adopted would not allow it a direct interaction with the H12. These contacts were mediated by one water molecule, suggesting this compound might also act as a partial agonist, independent of H12 interaction. All these findings may be explored for the design of PPARs novel modulators with lower side effects, as well, in the exploration of dual agonists PPAR±/³ that combines the therapeutic effects in the treatment of type 2 diabetes and dyslipidemia. (AU)