title: CHARMM Force Field Parameterization of Peroxisome Proliferator-Activated Receptor γ Ligands.
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.
authors.affiliation: Institute of Chemistry, University of Campinas-UNICAMP, P.O. Box 6154, Campinas 13082-864, SP, Brazil. melinamottin@gmail.com.|Faculty of Pharmacy, Federal University of Goias, Goiânia 74605-170, GO, Brazil. melinamottin@gmail.com.
authors.forename: Melina
authors.initials: M
authors.lastname: Mottin
authors.affiliation: Institute of Chemistry, University of Campinas-UNICAMP, P.O. Box 6154, Campinas 13082-864, SP, Brazil. paulocts@gmail.com.|Faculty of Mathematics and Natural Sciences, University of Groningen, Groningen 9747, AG, The Netherlands. paulocts@gmail.com.
authors.forename: Paulo C T
authors.initials: PC
authors.lastname: Souza
authors.affiliation: Institute of Chemistry, University of Campinas-UNICAMP, P.O. Box 6154, Campinas 13082-864, SP, Brazil. cla.g.ricci@gmail.com.|Department of Pharmacology, University of California San Diego-UCSD, San Diego, CA 92093, USA. cla.g.ricci@gmail.com.
authors.forename: Clarisse G
authors.initials: CG
authors.lastname: Ricci
authors.affiliation: Institute of Chemistry, University of Campinas-UNICAMP, P.O. Box 6154, Campinas 13082-864, SP, Brazil. skaf@iqm.unicamp.br.
authors.forename: Munir S
authors.initials: MS
authors.lastname: Skaf
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D062105:Molecular Docking Simulation; D047495:PPAR gamma / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C561901:(S)-4'-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-(1,1'-biphenyl)-2-carboxylic acid; C576055:5-(5-bromo-2-methoxybenzylidene)-3-(4-methyl-benzyl)thiazolidine-2,4-dione; D001713:Biphenyl Compounds; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones
keywords: CHARMM parameters; GQ16; PPARγ ligands; SR1664; molecular dynamics; nuclear receptor