基于分子对接的thanatin与NDM-1分子动力学模拟研究  

Molecular Dynamics Simulation of Thanatin and NDM-1 Based on Molecular Docking

作　　者：史祥睿 代宇婕 张弢 张庆华 刘威 Shi Xiangrui;Dai Yujie;Zhang Tao;Zhang Qinghua;Liu Wei(School of Chemical Engineering,Shenyang University of Chemical Techonlogy,Shenyang,110020;Reproductive Medicine Center,Daping Hospital,Army Medical University,Chongqing,400042;Institute of Immunology,Army Medical University,Chongqing,400038)

机构地区：[1]沈阳化工大学化学工程学院,沈阳110020 [2]陆军军医大学大坪医院生殖医学中心,重庆400042 [3]陆军军医大学全军免疫学研究所,重庆400038

出　　处：《化学通报》2021年第11期1237-1242,共6页Chemistry

基　　金：陆军军医大学临床技术创新培育项目(CX2019LC118)资助。

摘　　要：耐碳青霉烯类抗生素的超级细菌给人类健康带来了严重威胁,其所携带的金属β-内酰胺酶编码基因是耐药性的主要来源。NDM-1作为其中传播最广、活性最强的β-内酰胺酶,其抑制剂的研发刻不容缓。具有广谱作用的抗菌肽thanatin对NDM-1展现出了较好的抑制效果,但抑制机理并不清楚。本文使用HPEPDOCK与Rosetta FlexPepDock服务器,将thanatin与NDM-1进行了分子对接,并使用Desmond软件包对对接模型进行了分子动力学模拟。结果表明,thanatin与NDM-1活性中心的Zn^(2+)并无直接相互作用,而是作为竞争性抑制剂结合于NDM-1的活性口袋,阻止抗生素分子进入活性口袋与Zn^(2+)结合,从而抑制NDM-1的水解活性。本文为研发有效的NDM临床抑制剂探索了可行的方法。The carbapenem-resistant bacteria has posed serious threats to human health.This resistance mostly stems from plasmid-carried genes encoding metallo-β-lactamases(MBLs).As the most widespread MBL,NDM-1 shows highest activity ofβ-lactam hydrolysis and thus has become a hotspot for inhibitors development during the latest decades.Thanatin,a broad-spectrum antimicrobial peptide displays good inhibition efficacy against NDM-1,but the mechanism is still unknown.In this paper,we conducted molecular docking of thanatin to NDM-1 using the HPEPDOCK server and the Rosetta FlexPepDock server,followed by molecular dynamics simulation using the Desmond suite.Based on the analyses of the docked models and the MD trajectory,the results obtained from our calculation suggest that thanatin does not directly interact with Zn^(2+)in the active center of NDM-1,but acts as a competitive inhibitor binding to the active pocket of NDM-1,thereby preventing the binding of an antibiotic substrate to the Zn^(2+)and inhibiting the hydrolytic activity of NDM-1.This study may help researchers to find a feasible way to develop clinically efficient inhibitors of NDMs.

关 键 词：NDM-1 THANATIN 分子对接 动力学模拟 活性 

分 类 号：R91[医药卫生—药学]