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论文类型：期刊论文

发表时间：2014-09-01

发表刊物：INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

收录刊物：SCIE、PubMed、Scopus

卷号：15

期号：9

页面范围：15475-15502

ISSN号：1422-0067

关键字：MCHR1; 3D-QSAR; molecular docking; MD simulation

摘要：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 (Q(2)) = 0.509, non-cross-validated correlation coefficient (R-ncv(2)) = 0.841 and the predicted correlation coefficient (R-pred(2)) = 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.