Chemoinformatics and pharmacoinformatics approach for exploring the GABA-A agonist from Chinese herb suanzaoren
Chemoinformatics and pharmacoinformatics approach for exploring the GABA-A agonist from Chinese herb suanzaoren
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DOI：
10.1016/j.jtice.2008.07.011
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发表时间：
2009-01-01
影响因子：
5.7
通讯作者：
Chen, Calvin Yu-Chian
中科院分区：
文献类型：
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作者：
Chen, Calvin Yu-Chian
本研究首次通过同源建模构建了γ氨基丁酸A型（GABA-A）受体α 1/ γ 2界面的可靠结构，并对整个蛋白结构的各个环进行了细化。通过对接结合位点对照化合物、检测α 1/ γ 2界面关键残基、概率密度函数（PDF）值和Ramachandran图验证GABA-A受体模型的有效性。本文也首次采用化学信息学和药物信息学方法，提出酸枣仁汤的有效成分为大枣苷元，而不是大枣苷A和大枣苷B。此外，药效团分析表明，红枣素上的氧分别接近α 1-TYR160和γ 2-LYS184。比较分子场分析（CoMFA）模型在5组分下的q(cv)(2)值为0.731,r(2)值为0.942。比较分子相似性指数分析（CoMSIA）在5个组分上的q(cv)(2)为0.617,r(2)为0.921。CoMFA和CoMSIA模型结果具有统计学意义。因此，基于对接、ADMET描述子、药效团、三维定量构效关系（3D-QSAR）研究结果，推测红枣素可能是酸枣仁汤中有效的GABA-A激动剂。(c) 2008年台湾化学工程师学会。Elsevier B.V.版权所有。
This study is the first one to construct the reliable structure of the alpha 1/gamma 2 interface of Gamma aminobutyric acid type A (GABA-A) receptor by homology modeling and refined every loop of the whole protein structure. The modeling GABA-A receptor was validated by docking the control compounds in binding site, checking the key residue in alpha 1/gamma 2 interface, probability density function (PDF) value, and Ramachandran plot. This paper is also the first one to propose that jujubogenin is the effective component in suanzaoren decoction, neither jujuboside A nor jujuboside B by chemoinformatics and pharmacoinformatics approach. In addition, pharmacophore analysis showed that the oxygens on jujubogenin approached alpha 1-TYR160 and gamma 2-LYS184, respectively. The comparative molecular field analysis (CoMFA) model yielded a q(cv)(2) value of 0.731 and an r(2) of 0.942 at 5 components. Comparative molecular similarity indices analysis (CoMSIA) produced a q(cv)(2) of 0.617 and an r(2) of 0.921 at 5 components. The CoMFA and CoMSIA models showed statistically significant results. Hence, based on the results of docking, ADMET descriptor, pharmacophore, and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies, the jujubogenin was suggested to be the effective GABA-A agonist in suanzaoren decoction. (c) 2008 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.