Lin Feng, Li Feng, Wang Chao, Wang Jinghui, Yang Yinfeng, Yang Ling, Li Yan
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.
Molecules. 2017 Jun 26;22(7):1064. doi: 10.3390/molecules22071064.
As a G-protein coupled receptor, the 5-hydroxytryptamine 2A (5-HT) 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-HT 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 ² = 0.587, non-cross-validated correlation coefficient ² = 0.900 and predicted correlation coefficient for the test set of compounds ² = 0.897, respectively. Besides, molecular docking was also conducted to investigate the binding mode between these ligands and the active site of the 5-HT 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-HT 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-HT antagonists.
作为一种G蛋白偶联受体，5-羟色胺2A（5-HT）受体在认知、行为和生理功能中发挥着关键作用，因此是治疗精神疾病（尤其是抑郁症）的主要分子靶点。为了探索影响抑制活性的结构特征，目前建立了一个包含109种芳基哌嗪衍生物的数据集，这些衍生物有望成为5-HT拮抗剂，并在此基础上，采用比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）方法进行了基于配体的三维定量构效关系（3D-QSAR）研究。所得的最佳CoMSIA模型具有良好的有效性和可预测性，交叉验证相关系数² = 0.587，非交叉验证相关系数² = 0.900，化合物测试集的预测相关系数² = 0.897。此外，还进行了分子对接，以研究这些配体与5-HT受体活性位点之间的结合模式。同时，作为研究拮抗剂在结合腔中构象的对接补充工具，还进行了分子动力学（MD）模拟，进一步阐明了配体-受体复合物的变化。最后，基于上述结果还新设计了一些新分子，它们是潜在的5-HT受体芳基哌嗪拮抗剂。我们希望目前的模型和所得信息可能有助于促进新型强效拮抗剂作为抗抑郁药物的优化和设计，以及探索5-HT拮抗剂的相互作用机制。
