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

甲型流感病毒突变诱发的神经氨酸酶耐药性机制理论研究

作　　者：Song Luo Xiaoyu Zhao Yihui Wang Lili Duan 罗松;赵晓宇;王一惠;段莉莉(山东师范大学物理与电子科学学院,济南250014)

机构地区：[1]School of Physics and Electronics,Shandong Normal University,Jinan,250014,China

出　　处：《Chinese Journal of Chemical Physics》2021年第6期785-796,I0003,I0061-I0067,共20页化学物理学报（英文）

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

摘　　要：Influenza A(A/H_(x)N_(y))is a significant public health concern due to its high infectiousness and mortality.Neuraminidase,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 generated.Here,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 mutation.The 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 resistance.While in wild type(A/H7N9^(WT)),this hydrogen bond was initially stable.Meanwhile,N9 derived from A/H11N9 was obtained as an R292K mutation.Then 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 ASIE.In addition,Arg292 and Tyr406 were hot spots in the A/H11N9^(WT)-drugs.However,Lys292 was not observed as a favorable contributing residue in A/H11N9^(R292K),which may promote resistance.In 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 hotspots.This study could guide novel drug delivery of drug-resistant mutations in the treatment of A/H_(x)N9.

关 键 词：N9 Drug resistance Alanine-scanning-interaction-entropy method Binding free energy 

分 类 号：TQ460.1[化学工程—制药化工]