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Int. J. Mol. Sci. 2017, 18(1), 15; doi:10.3390/ijms18010015

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

1
Institute of Chemistry, University of Campinas—UNICAMP, P.O. Box 6154, Campinas 13082-864, SP, Brazil
2
Faculty of Pharmacy, Federal University of Goias, Goiânia 74605-170, GO, Brazil
3
Faculty of Mathematics and Natural Sciences, University of Groningen, Groningen 9747, AG, The Netherlands
4
Department of Pharmacology, University of California San Diego—UCSD, San Diego, CA 92093, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Christo Z. Christov
Received: 18 October 2016 / Revised: 15 December 2016 / Accepted: 16 December 2016 / Published: 22 December 2016
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
View Full-Text   |   Download PDF [3974 KB, uploaded 22 December 2016]   |  

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. View Full-Text
Keywords: PPARγ ligands; nuclear receptor; CHARMM parameters; molecular dynamics; GQ16; SR1664 PPARγ ligands; nuclear receptor; CHARMM parameters; molecular dynamics; GQ16; SR1664
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Mottin, M.; Souza, P.C.T.; Ricci, C.G.; Skaf, M.S. CHARMM Force Field Parameterization of Peroxisome Proliferator-Activated Receptor γ Ligands. Int. J. Mol. Sci. 2017, 18, 15.

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