IDH1R132H突变蛋白与其抑制剂AG-881的分子动力学模拟研究  

Molecular dynamics simulation study of IDH1R132H mutant protein and its inhibitor AG-881

作　　者：邵婷婷 孔晓华 靳京 孟凡翠 刘巍[2,3,4] SHAO Ting-ting;KONG Xiao-hua;JIN Jing;MENG Fan-cui;LIU Wei(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;State Key Laboratory of Drug Delivery Technology and Pharmacokinetics,Tianjin Institute of Pharmaceutical Research,Tianjin 300301,China;Tianjin Institute of Pharmaceutical Research,Research Unit for Drug Metabolism,Chinese Academy of Medical Sciences,Tianjin 300301,China)

机构地区：[1]天津医科大学药学院,天津300070 [2]天津药物研究院有限公司天津市新药设计与发现重点实验室,天津300450 [3]释药技术与药动学国家重点实验室,天津300301 [4]天津药物研究院中国医学科学院药物代谢新技术创新单元,天津300301

出　　处：《中国新药杂志》2023年第6期610-617,共8页Chinese Journal of New Drugs

基　　金：中国医学科学院医学与健康科技创新工程项目(2019-I2M-5-020)。

摘　　要：目的:采用分子动力学模拟方法研究化合物AG-881(vorasidenib)抑制IDH1R132H突变蛋白的作用机制。方法:分别构建激活态的IDH1R132H突变蛋白结构和失活态的AG-881-IDH1R132H突变蛋白结构,置于立体水盒子内,进行100 ns的分子动力学模拟,比较不同体系的蛋白构象并分析氢键、能量和主成分等性质。结果:底物α-KG可使IDH1R132H突变蛋白稳定在活化状态的闭合构象。AG-881作用于蛋白二聚体界面的变构位点后,使IDH1R132H突变蛋白处于非活化状态的开放构象,发挥抑制作用。在作用过程中,氨基酸残基Gln277在AG-881的结合中起重要作用。同时,疏水作用和氢键在AG-881与IDH1R132H突变蛋白的结合中也做出重要贡献。此外,卤键也起到一定作用。结论:分子动力学模拟可以作为变构抑制剂设计的有效辅助手段,探索研究AG-881抑制IDH1R132H突变蛋白活性的潜在作用机制,进一步为以IDH1突变蛋白为靶点的新药研发提供一定的理论指导。Objective:To investigate the mechanism of compound AG-881 on inhibiting IDHIR132H mutant protein by molecular dynamics method.Methods:The activated IDHIR132H protein structure and inactivated AG-881-IDHIR132H protein structure were constructed respectively and placed in a stereoscopic box.Molecular dynamics simulations were carried out on each system for 100 ns.The protein conformations of different systems were compared,and hydrogen bond analysis,energy analysis and principal component analysis(PCA),etc.were performed.Results:Substrate α-KG could stabilize IDHIR132H protein in the activated closed conformation.After AG-881 acted on the allosteric site of the protein at dimer interface,it made IDHIR132H in the open conformation of inactive state.In this process,amino acid residue Gln277 participated into the binding of AG-881.At the same time,hydrophobic occupation and hydrogen bond contributed mainly to the binding of AG-881 to IDHIR132H.In addition,halogen bond also played a certain role.Conclusion:Molecular dynamics simulation can be used as an effective aid for allosteric inhibitor design,and the potential mechanism of AG-881 inhibiting IDHIR132H activity can be studied,which can further provide theoretical guidance for the development of new drugs targeting IDH1 mutant proteins.

关 键 词：异柠檬酸脱氢酶1 分子动力学 AG-881 氨基酸残基 变构位点 

分 类 号：R965[医药卫生—药理学]