Wu Mingwei, Li Yan, Fu Xinmei, Wang Jinghui, Zhang Shuwei, Yang Ling
Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), Dalian University of Technology, Dalian 116024, China.
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China.
Int J Mol Sci. 2014 Sep 1;15(9):15475-502. doi: 10.3390/ijms150915475.
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.
黑色素聚集激素受体1（MCHR1）是能量稳态的关键调节因子，参与进食和能量代谢的控制，是治疗肥胖症的一个有前景的靶点。在本研究中，对目前最大的一组181种喹啉/喹唑啉衍生物作为MCHR1拮抗剂进行了基于配体和受体的三维定量构效关系（3D-QSAR）分析，应用了比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）。最佳可预测的CoMSIA模型具有显著的有效性，交叉验证相关系数（Q²）=0.509，非交叉验证相关系数（R²(ncv)）=0.841，预测相关系数（R²(pred)）=0.745。此外，进行了对接研究和分子动力学（MD）模拟，以进一步阐明MCHR1拮抗剂的结合模式。在水和脂质双层系统中都进行了MD模拟。我们希望所获得的模型和信息有助于深入了解MCHR1拮抗剂的相互作用机制，并促进新型拮抗剂作为抗肥胖药物的设计和优化。
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