人类胞外信号调节激酶1的同源模建及其抑制剂的对接与结构改造  

Homology Modeling of Human Extracellular Signal-regulated Kinase 1 and Docking and Reconstitution of Its Inhibitors

作　　者：张继龙[1] 侯瑞哲[2] 李卓[1] 郑清川[1] 张红星[1] 

机构地区：[1]吉林大学理论化学研究所理论化学计算国家重点实验室,长春130023 [2]吉林大学白求恩医学院,长春130021

出　　处：《化学学报》2010年第3期222-226,共5页Acta Chimica Sinica

基　　金：国家自然科学基金(No20903045;20573042);国家科技支撑计划重点项目(No2006BAE03B01);高等学校博士点学科专项基金(No20070183046);吉林大学基本科研业务费(No200810018)资助项目

摘　　要：通过同源模建和分子动力学模拟构建了人类胞外信号调节激酶1(hERK1)的三维结构,并利用profile-3D和procheck方法评估了模型的合理性.对所得的结构使用分子对接程序Affinity和CDOCKER进行了两种抑制剂的对接.结果显示这两种抑制剂与酶的结合方式相似,它们均与残基K36,Q87之间存在氢键作用,二者取代基的不同导致了抑制能力的差别.基于对接结果分析,对已知抑制剂进行结构改造,得到了一个理论上结合能力更强的抑制剂.它在保持与K36和Q87之间氢键的同时,又与残基D93,K96,S135形成了四条氢键,显著提高了与酶的相互作用.对接相互作用能显著下降,MM-PBSA结合自由能降为负值,这些均体现了抑制能力的提高.本工作对于针对该酶的抑制剂设计和相关疾病的新药开发具有理论指导价值.The three dimensional structure of human extracellular signal-regulated kinase 1（hERK1） was modeled and refined using homology modeling and molecular dynamics simulation.The model was assessed by profile-3D and procheck methods,which confirmed that the obtained model was reliable.Two inhibitors were docked into the refined structure by the molecular docking programs,Affinity and CDOCKER.The results show that the two inhibitors share the similar binding pattern,which interact with the residues K36 and Q87 by hydrogen bonds.Their different substituent groups lead to the different affinities with hERK1.The reconstitution of the known inhibitor,on the basis of docking result,produces a new inhibitor,which binds to hERK1 more strongly,reserves the hydrogen bonds with K36 and Q87 at the same time to form four hydrogen bonds with the residues D93,K96 and S135,significantly increasing the interaction with hERK1.The docking energies of Affinity and CDOCKER significantly decrease,even the binding free energy of MM-PBSA decreases to be the negative value.All the energy changes show the raise of inhibiting capacity.This work provided the theoretical guidance for the inhibitor design of hERK1 and the development of the new drug for the related diseases.

关 键 词：人类胞外信号调节激酶1 同源模建 分子动力学 对接 抑制剂 

分 类 号：R363[医药卫生—病理学]