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SANTOS, J. C. Structural characterization of the peroxisome proliferator-activated receptors (PPARs) types alpha and gamma complexes and its agonists. 2014. 131p. Tese (Doutorado em Ciências) Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, 2014. 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: PPARα, PPARβ e PPARγ. PPARγ 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 PPARα and are used to lower serum triglyceride levels. Most of these 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 PPARα and PPARγ 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, α and γ. Thus, this study reveals the structural basis for this dual agonist GL479 by structural determination of the complexes PPARα-LBD:GL479 and PPARγ-LBD:GL479. The detailed analysis of these complexes showed different ligand binding modes for each receptor, however, in both cases the GL479 interacted with the Tyr of H12. In the PPARα-LBD structure the ligand acquired the features of full agonist and in the case of PPARγ-LBD, GL479 adopted features of a partial agonist dependent of H12 interaction. In addition to the dual agonist analysis, sixteen compounds were identified as PPARγ ligand by docking. Three of these ligands were characterized by ThermoFluor and fluorescence polarization, which resulted in IC50 values smaller than 10 μM. Additionally, one of the compounds, identified by docking, was co-crystallized with PPARγ. The ligand conformation adopted did 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 PPARα/γ that combines the therapeutic effects in the treatment of type 2 diabetes and dyslipidemia.

Caracterização estrutural dos complexos entre os receptores ativadores da proliferação de peroxissomos (PPARs) dos tipos alfa e gama e seus agonistas