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Molecules 2017, 22(7), 1064;

Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods

Key Laboratory of Xinjiang Endemic Phytomedicine Resources, Pharmacy School, Shihezi University, Shihezi 832002, Xinjiang, China
Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), Faculty of Chemical, Environmental and Biological Science and Technology, Dalian University of Technology, Dalian 116024, Liaoning, China
Department of Civil Engineering, Henan Institute of Engineering, Zhengzhou 451191, Henan, China
Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Author to whom correspondence should be addressed.
Received: 21 April 2017 / Revised: 23 June 2017 / Accepted: 23 June 2017 / Published: 26 June 2017
(This article belongs to the Special Issue Biomolecular Simulations)
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As a G-protein coupled receptor, the 5-hydroxytryptamine 2A (5-HT2A) receptor is known for its critical role in the cognitive, behavioural and physiological functions, and thus is a primary molecular target to treat psychiatric diseases, including especially depression. With purpose to explore the structural traits affecting the inhibitory activity, currently a dataset of 109 arylpiperazine derivatives as promising 5-HT2A antagonists was built, based on which the ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) study by using both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches was carried out. The resultant optimal CoMSIA model displays proper validity and predictability with cross-validated correlation coefficient Q2 = 0.587, non-cross-validated correlation coefficient R2ncv = 0.900 and predicted correlation coefficient for the test set of compounds R2pre = 0.897, respectively. Besides, molecular docking was also conducted to investigate the binding mode between these ligands and the active site of the 5-HT2A receptor. Meanwhile, as a docking supplementary tool to study the antagonists’ conformation in the binding cavity, molecular dynamics (MD) simulation was also performed, providing further elucidation about the changes in the ligand-receptor complex. Lastly, some new molecules were also newly-designed based on the above results that are potential arylpiperazine antagonists of 5-HT2A receptor. We hope that the present models and derived information may be of help for facilitating the optimization and design of novel potent antagonists as antidepressant drugs as well as exploring the interaction mechanism of 5-HT2A antagonists. View Full-Text
Keywords: depression; 5-HT2A receptor; arylpiperazine derivative; 3D-QSAR; molecular docking; molecular dynamics depression; 5-HT2A receptor; arylpiperazine derivative; 3D-QSAR; molecular docking; molecular dynamics

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Lin, F.; Li, F.; Wang, C.; Wang, J.; Yang, Y.; Yang, L.; Li, Y. Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods. Molecules 2017, 22, 1064.

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