胰高血糖素样肽-1受体的分子动力学模拟研究  

Molecular dynamics simulation study of glucagon-like peptide-1 receptor

作　　者：都宵晓 孟凡翠[2] 刘巍[2] 汤立达[2] DU Xiao-xiao;MENG Fan-cui;LIU Wei;TANG Li-da(Pharmacy College,Tianjin Medical University,Tianjin 300070,China;Tianjin Key Laboratory of Molecular Design and Drug Discovery,Tianjin Institute of Pharmaceutical Research,Tianjin 300450,China)

机构地区：[1]天津医科大学药学院,天津300070 [2]天津药物研究院天津市新药设计与发现重点实验室,天津300450

出　　处：《中国新药杂志》2021年第8期732-739,共8页Chinese Journal of New Drugs

基　　金：天津市新药创制科技重大专项(18ZXXYSY00040)。

摘　　要：目的:采用分子动力学模拟方法研究胰高血糖素样肽-1受体(GLP-1R)的激活机制。方法:分别构建激活态和失活态的GLP-1R结构,置于棕榈酰-油酰-卵磷脂(POPC)双层膜内,进行50 ns的分子动力学模拟,比较不同体系的构象并进行氢键、能量、主成分等性质分析。结果:结果表明失活态的胞外域整体倒向跨膜区,激活态和失活态的胞内第三loop(ICL3)构象差异明显,可见ICL3在GLP-1R的激活中扮演着重要角色。氢键和能量分析结果均表明胰高血糖素样肽-1(GLP-1)的His7*,Glu9*和Asp15*在与GLP-1R的结合中起着较为重要的作用。结论:分子动力学模拟作为辅助手段可用于研究GLP-1R构象变化对其自身激活的影响以及GLP-1与受体结合时的激活机制,为以GLP-1R为靶点的药物研发提供一定的理论指导。Objective:To investigate the activation mechanism of glucagon-like peptide-1 receptor(GLP-1R)by molecular dynamics method.Methods:The active and inactive states of GLP-1R were constructed and embedded in a palmitoyl oleoyl phosphatidyl choline(POPC)bilayer.Molecular dynamics simulations were carried out on each system for 50 ns.Conformations of active and inactive states were compared,and hydrogen bond analysis,energy analysis and principal component analysis etc.were performed.Results:Conformation analysis showed that the N-terminal ectodomain of GLP-1R moved to the transmembrane domain in inactive state.The third intracellular loop(ICL3)was different between active and inactive states of GLP-1R,suggesting that ICL3 played a significant role in the activation of GLP-1R.The outcomes of hydrogen bond analysis and energy analysis indicated that His7*,Glu9*and Asp15*of GLP-1 were important in the binding of GLP-1R.Conclusion:Molecular dynamics method can be used as a supplementary tool to study the effects of GLP-1R conformational changes on its own activation and the activation mechanism of GLP-1 binding to receptors,providing theoretical guidance for the development of drugs targeting GLP-1R.

关 键 词：胰高血糖素样肽-1受体 激活态 失活态 分子动力学 药物 

分 类 号：R965.1[医药卫生—药理学]