Homology modeling and explicit membrane molecular dynamics simulation to delineate the mode of binding of thiazolidinediones into FFAR1 and the mechanism of receptor activation |
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| Institution: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt;2. Eli & Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, 1425 San Pablo Street, BCC 505, Los Angeles, CA 90033, USA;1. Laboratoire de Physique des Matériaux et Modélisation des Systèmes (LP2MS), Unité Associée au CNRST-URAC 08, Physics Department, Faculty of Sciences, University of Moulay Ismail, B.P. 11201 Meknes, Morocco;2. Max-Planck-Institut für Physik Complexer Systeme, Nöthnitzer Str. 38 D-01187 Dresden, Germany;3. Condensed Matter Theory Group, Department of Physics and Astronomy, Uppsala University, 75120 Uppsala, Sweden;1. Institute of Traditional Chinese Medicine & Natural Products, Jinan University, China;2. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, China;3. College of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, China;1. GlaxoSmithKline, Philadelphia, PA;2. Xcenda, LLC, Palm Harbor, FL |
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| Abstract: | Free fatty acid receptor 1 (FFAR1) is a member of a previously characterized cluster of orphan G protein-coupled receptors (GPCRs). Later, this orphan receptor was identified as a target of medium- to long-chain free fatty acids in β-cells of the pancreas. Administration of FFAR1 agonists has been proved to potentiate glucose-stimulated insulin secretion from pancreatic β-cells. It was reported that some thiazolidinediones (TZDs), the best studied PPARγ agonists, are also able to stimulate FFAR1 in a dose-dependent manner. In the present study, a homology model of the human FFAR1 was constructed and inserted into a pre-equilibrated DPPC/TIP3P membrane system. This system was then simulated for 20 ns in complex with the FFAR1 agonist GW9085, as well as rosiglitazone and pioglitazone. We noticed that the salt bridge between Glu172 and Arg258 and the H bond between Glu145 and His153 could be responsible for the stabilization of the receptor in the inactive state. Moreover, we described for the first time the binding mode of TZDs in the binding site of FFAR1. The thiazolidinedione head forms a hydrogen bonding network with the critical polar residues in the binding site, Arg258 and Asn244, while the rest of the molecule is embedded into the receptor hydrophobic pocket. Based on this modeling study, we arrived at a proposal of the pharmacophore required for binding to both PPARγ and FFAR1. Insights gained from this investigation should provide future directions for the design of novel dual acting antidiabetic agents. |
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| Keywords: | Diabetes FFAR1 PPARγ Thiazolidinediones Molecular dynamics |
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