title: Insight into analysis of interactions of GW9508 to wild-type and H86F and H137F GPR40: a combined QM/MM study and pharmacophore modeling.
abstract: GPR40 is a novel potential target for the treatment of type 2 diabetes. In this work, a two-layered ONIOM based QM/MM approach was employed to study the interactions between GW9508 and GPR40: wild-type, H86F, and H137F mutated systems. The calculated results clearly indicated that His137 is directly involved in ligand recognition through the NH-π interaction with the GW9508. In contrast, His86 is not interacting with the GW9508 in the NH-π interaction. The interaction energies, calculated at the MP2/6-31(d, p) level, were performed to gain more insight into the energetic differences of the wild-type and two mutated systems at the atomistic level. In addition, the obtained pharmacophore model was well consistent with structure-functional requirements for the binding of GPR40 agonists and with per-residue energy decomposition of the ONIOM calculations.
authors.affiliation: Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, PR China.
authors.forename: Shao-Yong
authors.initials: SY
authors.lastname: Lu
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Jiang
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Zou
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
authors.forename: Tian-Xing
authors.initials: TX
authors.lastname: Wu
mesh_terms: D001665:Binding Sites; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D055808:Drug Discovery; D004347:Drug Interactions; D008744:Methylamines / Q000737:chemistry* / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D011422:Propionates / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011789:Quantum Theory; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: C473034:FFAR1 protein, human; C515630:GW9508; D008744:Methylamines; D011422:Propionates; D043562:Receptors, G-Protein-Coupled