基于计算机辅助水解的中药大豆寡肽的ETA拮抗活性预测  

Prediction of ETA oligopeptides antagonists from Glycine max based on in silico proteolysis

作　　者：乔连生[1] 蒋芦荻 雒刚刚 路芳[1] 陈艳昆 王灵芝[1] 李贡宇[1] 张燕玲[1] QIAO Lian-sheng JIANG Lu-di LUO Gang-gang LU Fang CHEN Yan-kun WANG Ling-zhi LI Gong-yu ZHANG Yan-ling(Key Laboratory of Traditional Chinese Medicine Foundation and New Drug Research, School oJ＂ Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China)

机构地区：[1]北京中医药大学中药学院中药基础与新药研究重点实验室,北京100102

出　　处：《中国中药杂志》2017年第4期746-751,共6页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金项目(81173522;81573831);北京市教育委员会共建项目;北京中医药大学研究生自主课题(2016-JYBXS088)

摘　　要：中药寡肽是中药发挥药效的关键组分之一,系统地研究中药寡肽的组成及其药效是中药物质基础及作用机制研究的关键。该研究拟基于计算机辅助水解和分子对接等模拟技术,以中药大豆为研究载体,解析其降压寡肽成分,并预测其潜在的内皮素受体A(endothelin receptor A,ETA)拮抗活性。该文通过收集大豆中的储存蛋白序列,基于计算机辅助水解方法进行蛋白的模拟消化水解,并将水解获得的寡肽构建虚拟结构数据库。随后该研究构建了ETA肽类拮抗剂的药效团模型,包括1个疏水特征、1个负电中心、1个芳环特征和5个排除体积。同时,利用同源模建方法构建ETA的蛋白三维结构模型,并将其用于分子对接研究,采用一致性打分评价化合物的ETA拮抗活性。通过构建ETA肽类拮抗剂的药效团模型、同源模建的三维蛋白结构以及分子对接模型,共预测获得27条可能具有潜在ETA拮抗活性的寡肽分子。该文进一步分析关键氨基酸GLN165,并结合文献,说明其对拮抗剂活性的重要性。计算机辅助水解方法可以高效地对已知序列结构的中药蛋白进行模拟水解,结合分子模拟模型,能进一步辨识中药寡肽潜在的生物学活性。该研究为快速、高效开展中药来源的肽类物质的活性机制研究提供了方法学依据。Oligopeptides are one of the the key pharmaceutical effective constituents of traditional Chinese medicine（ TCM）. Systematic study on composition and efficacy of TCM oligopeptides is essential for the analysis of material basis and mechanism of TCM. In this study,the potential anti-hypertensive oligopeptides from Glycine max and their endothelin receptor A（ ETA） antagonistic activity were discovered and predicted based on in silico technologies. Main protein sequences of G. max were collected and oligopeptides were obtained using in silico gastrointestinal tract proteolysis. Then,the pharmacophore of ETA antagonistic peptides was constructed and included one hydrophobic feature,one ionizable negative feature,one ring aromatic feature and five excluded volumes. Meanwhile,three-dimensional structure of ETA was developed by homology modeling methods for further docking studies. According to docking analysis and consensus score,the key amino acid of GLN165 was identified for ETA antagonistic activity. And 27 oligopeptides from G.max were predicted as the potential ETA antagonists by pharmacophore and docking studies. In silico proteolysis could be used to analyze the protein sequences from TCM. According to combination of in silico proteolysis and molecular simulation,the biological activities of oligopeptides could be predicted rapidly based on the known TCM protein sequence. It might provide the methodology basis for rapidly and efficiently implementing the mechanism analysis of TCM oligopeptides.

关 键 词：计算机辅助水解 寡肽 大豆 内皮素受体A 药效团 同源模建 分子对接 

分 类 号：R284[医药卫生—中药学]