1 research outputs found
A computational study to identify the key residues of peroxisome proliferator-activated receptor gamma in the interactions with its antagonists
<p>Peroxisome proliferator-activated receptors (PPARs) compose a family of nuclear receptors, PPARĪ±, PPARĪ², and PPARĪ³, which mediate the effects of lipidic ligands at the transcriptional level. Among these, the PPARĪ³ has been known to regulate adipocyte differentiation, fatty acid storage and glucose metabolism, and is a target of antidiabetic drugs. In this work, the interactions between PPARĪ³ and its six known antagonists were investigated using computational methods such as molecular docking, molecular dynamics (MD) simulations, and the hybrid quantum mechanics/molecular mechanics (QM/MM). The binding energies evaluated by molecular docking varied between ā22.59 and ā35.15Ā kJĀ mol<sup>āā1</sup>. In addition, MD simulations were performed to investigate the binding modes and PPARĪ³ conformational changes upon binding of antagonists. Analysis of the root-mean-square fluctuations (<i>RMSF</i>) of backbone atoms shows that H3 of PPARĪ³ has a higher mobility in the absence of antagonists and moderate conformational changes were observed. The interaction energies between antagonists and each PPARĪ³ residue involved in the interactions were studied by QM/MM calculations. These calculations reveal that antagonists with different structures show different interaction energies with the same residue of PPARĪ³. Therefore, it can be concluded that the key residues vary depending on the structure of the ligand, which binds to PPARĪ³.</p