The Peroxisome Proliferator Activated Receptors gamma (PPAR gamma) is an important nuclear receptor which enhances insulin sensitivity, regulates the levels of plasma glucose and catches/stores lipids in peripheral tissues. Thus, the PPAR gamma consists of a molecular target for developing new drugs for treating type 2 diabetes. Among the ligands of this receptor, the full agonists, cause undesirable side effects such as weight gain, edema and congestive heart failure, although they reduce systemic insulin resistance. Therefore, partial agonists are interesting alternatives, because they retain the therapeutic effects of insulin sensitization without presenting the typical side effects of full agonists. Recent studies show that some structural characteristics are important for the receptor ligand-specific activation. One of these auxiliary factors of the activation is related to the phosphorylation of a serine of the receptor mediated by a protein kinase, CDK5. This is a very promising subject, as it allows integrating PPAR gamma interaction with another protein, CDK5, enabling a global view of the system. Our main objectives in this project aim to understand the molecular mechanisms involved in the phosphorylation reaction of S245 by cdk5 and understand how different ligands can inhibit more (or less) effectively the phosphorylation of this residue. For that goal, we propose using molecular dynamics simulations and hybrid quantum-classical simulations (QM / MM, Quantum Mechanics-Molecular Mechanics) to investigate PPARgamma and its association to Cdk5 and the effect of ligands on this enzyme-protein association.
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