结核分枝杆菌EPSP合酶与草甘膦的分子对接研究

Study on molecular docking between Mycobacterium tuberculosis EPSP synthase and the glyphosate

采用Autodock4.2分子对接软件包,对结核分枝杆菌5-烯醇式丙酮酰莽草酸-3-磷酸合酶(5-Enolpyruvylshikimate-3-phosphate synthase,简称EPSP合酶)和草甘膦的相互作用机制进行了分子对接研究.研究结果表明,草甘膦与结核分枝杆菌EPSP合酶结合能为-28.27kcal/mol;结合位点位于该酶底物磷酸烯醇式丙酮酸(PEP)的结合位点上,并与底物形成竞争性结合;草甘膦能与结核分枝杆菌EPSP合酶中位于活性空腔的Glu311,His340,Thr97及Arg124等11个氨基酸残基及酶底物S3P形成疏水作用;结核分枝杆菌EPSP合酶中Arg385,Arg344,His384,Lys23,Gly96,Arg124,Lys410,Glu341 8个氨基酸残基能与草甘膦上的羧基及磷酸基团形成10个氢键,推测草甘膦的羧基及磷酸基团是草甘膦对EPSP合酶抑制作用的物质基础;草甘膦与结核分枝杆菌EPSP合酶结合的主要推动力为氢键、疏水作用及静电作用力.研究结果可为草甘膦的结构改良及EPSP合酶基因的改造提供理论参考,并为通过对莽草酸途径的抑制作用这一崭新方法来研发新型抗结核药物提供科学依据.

Molecular docking was used to investigate the interaction mechanism between Mycobacterium tuberculosis EPSP synthase and glyphosate by Autodock 4.2program.This study result showed that docking glyphosate into the active site of Mycobacterium tuberculosis EPSP synthase yielded a docking free energy of-28.27kJ/mol;Glyphosate located to the binding site of the substrate PEP and competitively binded with PEP in Mycobacterium tuberculosis EPSP synthase;Glyphosate can produce hydrophobic interactions with the the residues in the binding pocket（such as Glu311,His340,Thr97,Arg124,etc）and the substrate S3P;The eight residues（Arg385,Arg344,His384,Lys23,Gly96,Arg124,Lys410,Glu341）of Mycobacterium tuberculosis EPSP synthase can form ten H-bonds with the carboxyl and phosphate group of glyphosate,which can speculated that the carboxyl and phosphate group of glyphosate was the material basis of inhibition of Mycobacterium tuberculosis EPSP synthase by glyphosate;The main driving force of binding between Mycobacterium tuberculosis EPSP synthase and glyphosate were hydrogenbond,hydrophobic interactions and electrostatic forces.The result of our simulation will provide theoretical basis for molecular structure improvement of glyphosate and genetic modification of EPSP synthase,and through the new approach of inhibition of shikimic acid way to provide a scientific basis for developing anti-tuberculosis drugs.