Theoretical Investigating Mechanisms of Drug-Resistance Generated by Mutation-Induced Changes in Influenza Viruses

作     者：Song Luo Xiaoyu Zhao Yihui Wang Lili Duan 罗松;赵晓宇;王一惠;段莉莉

作者机构：School of Physics and ElectronicsShandong Normal UniversityJinan250014China 

出 版 物：《Chinese Journal of Chemical Physics》 (化学物理学报（英文）)

年 卷 期：2021年第34卷第6期

页      面：785-796,I0003,I0061-I0067页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(No.11774207) 

主　　题：N9 Drug resistance Alanine-scanning-interaction-entropy method Binding free energy 

摘      要：Influenza A(A/H_(x)N_(y))is a significant public health concern due to its high infectiousness and ***,which interacts with sialic acid(SIA)in host cells,has become an essential target since its highly conserved catalytic center structure,while resistance mutations have already ***,a detailed investigation of the drug resistance mechanism caused by mutations was performed for subtype N9(A/H7N9).Molecular dynamics simulation and alanine-scanning-interaction-entropy method(ASIE)were used to explore the critical differences between N9 and Zanamivir(ZMR)before and after R294K *** results showed that the mutation caused the hydrogen bond between Arg294 and ZMR to break,then the hydrogen bonding network was disrupted,leading to weakened binding ability and *** in wild type(A/H7N9^(WT)),this hydrogen bond was initially ***,N9 derived from A/H11N9 was obtained as an R292K *** the relative binding free energy of N9 with five inhibitors(SIA,DAN,ZMR,G28,and G39)was predicted,basically consistent with experimental values,indicating that the calculated results were reliable by *** addition,Arg292 and Tyr406 were hot spots in the A/H11N9^(WT)-***,Lys292 was not observed as a favorable contributing residue in A/H11N9^(R292K),which may promote *** comparison,Tyr406 remained the hotspot feature when SIA,ZMR,and G28 binding to A/H11N9^(R292K).Combining the two groups,we speculate that the resistance was mainly caused by the disruption of the hydrogen bonding network and the transformation of *** study could guide novel drug delivery of drug-resistant mutations in the treatment of A/H_(x)N9.