CHARMM Force Field Parameterization of Peroxisome Proliferator-Activated Receptor ? Ligands.

ABSTRACT: The peroxisome proliferator-activated receptor ? (PPAR?) ligands are important therapeutic drugs for the treatment of type 2 diabetes, obesity and cardiovascular diseases. In particular, partial agonists and non-agonists are interesting targets to reduce glucose levels, presenting few side effects in comparison to full agonists. In this work, we present a set of CHARMM-based parameters of a molecular mechanics force field for two PPAR? ligands, GQ16 and SR1664. GQ16 belongs to the thiazolidinedione class of drugs and it is a PPAR? partial agonist that has been shown to promote the "browning" of white adipose tissue. SR1664 is the precursor of the PPAR? non-agonist class of ligands that activates PPAR? in a non-classical manner. Here, we use quantum chemical calculations consistent with the CHARMM protocol to obtain bonded and non-bonded parameters, including partial atomic charges and effective torsion potentials for both molecules. The newly parameterized models were evaluated by examining the behavior of GQ16 and SR1664 free in water and bound to the ligand binding pocket of PPAR? using molecular dynamics simulations. The potential parameters derived here are readily transferable to a variety of pharmaceutical compounds and similar PPAR? ligands.

SUBMITTER: Mottin M 

PROVIDER: S-EPMC5297650 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature