title: Profiling the interaction mechanism of quinoline/quinazoline derivatives as MCHR1 antagonists: an in silico method.
abstract: Melanin concentrating hormone receptor 1 (MCHR1), a crucial regulator of energy homeostasis involved in the control of feeding and energy metabolism, is a promising target for treatment of obesity. In the present work, the up-to-date largest set of 181 quinoline/quinazoline derivatives as MCHR1 antagonists was subjected to both ligand- and receptor-based three-dimensional quantitative structure-activity (3D-QSAR) analysis applying comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The optimal predictable CoMSIA model exhibited significant validity with the cross-validated correlation coefficient (Q²) = 0.509, non-cross-validated correlation coefficient (R²(ncv)) = 0.841 and the predicted correlation coefficient (R²(pred)) = 0.745. In addition, docking studies and molecular dynamics (MD) simulations were carried out for further elucidation of the binding modes of MCHR1 antagonists. MD simulations in both water and lipid bilayer systems were performed. We hope that the obtained models and information may help to provide an insight into the interaction mechanism of MCHR1 antagonists and facilitate the design and optimization of novel antagonists as anti-obesity agents.
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), Dalian University of Technology, Dalian 116024, China. audi.lg@163.com.
authors.forename: Mingwei
authors.initials: M
authors.lastname: Wu
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), Dalian University of Technology, Dalian 116024, China. yanli@dlut.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China. fuxinmei@dlut.edu.cn.
authors.forename: Xinmei
authors.initials: X
authors.lastname: Fu
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), Dalian University of Technology, Dalian 116024, China. jhwang_dlut@163.com.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), Dalian University of Technology, Dalian 116024, China. zswei@dlut.edu.cn.
authors.forename: Shuwei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences, Dalian 116023, China. yling@dicp.ac.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D019440:Anti-Obesity Agents / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D016018:Least-Squares Analysis; D008051:Lipid Bilayers; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D055672:Static Electricity; D014867:Water
chemical_list: D019440:Anti-Obesity Agents; D008051:Lipid Bilayers; C103263:MCHR1 protein, human; D011799:Quinazolines; D011804:Quinolines; D017481:Receptors, Somatostatin; D014867:Water