CHARMM Force Field Parameterization of Peroxisome Proliferator-Activated Receptor γ Ligands

Melina Mottin,Munir Skaf,Clarisse Ricci,Paulo Souza

doi:10.3390/ijms18010015

Abstract

The peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ ligands, GQ16 and SR1664. GQ16 belongs to the thiazolidinedione class of drugs and it is a PPARγ partial agonist that has been shown to promote the “browning” of white adipose tissue. SR1664 is the precursor of the PPARγ non-agonist class of ligands that activates PPARγ 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 PPARγ using molecular dynamics simulations. The potential parameters derived here are readily transferable to a variety of pharmaceutical compounds and similar PPARγ ligands.

Highlights

The peroxisome proliferator-activated receptor γ (PPARγ) is an important nuclear receptor (NR) which plays a major role in the regulation of glucose and lipid metabolisms [1,2,3,4]
The serine 245 residue, located in the PPARγ ligand binding domain (LBD), is a recently discovered phosphorylation site [8] and it can be modified by the enzymes Cyclin-Dependent Kinase 5 (Cdk5) [6,8] and Extracellular Signal-Regulated Kinase (ERK) [9]
A recent study reported that GQ16 can increase brown adipose tissue (BAT) activity and induce the expression of thermogenesis-related genes in visceral white adipocyte tissue (WAT) [23]. These findings suggest that PPARγ activity might be modulated by partial agonists to induce WAT browning and treat obesity [23]

Summary

Introduction

The peroxisome proliferator-activated receptor γ (PPARγ) is an important nuclear receptor (NR) which plays a major role in the regulation of glucose and lipid metabolisms [1,2,3,4]. It has implications in different metabolic disorders such as diabetes, obesity, and cardiovascular diseases [1,5]. The classical ligand-dependent activation involves inducing conformational changes in the ligand binding domain (LBD), especially in the helix 12 (H12). This structural rearrangement leads to the dissociation of corepressors and the recruitment of coactivators. The serine 245 residue, located in the PPARγ LBD, is a recently discovered phosphorylation site [8] and it can be modified by the enzymes Cyclin-Dependent Kinase 5 (Cdk5) [6,8] and Extracellular Signal-Regulated Kinase (ERK) [9]

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Conclusion