H1N1流感病毒D151G突变株对奥司他韦的抗药性研究及药物筛选

Drug resistance of mutation D151G of H1N1 influenza virus to oseltamivir and drug screening

目的:观察H1N1流感病毒D151G突变株对奥司他韦的抗药性,筛选对D151G突变神经氨酸酶具有抑制作用的化合物。方法:采用分子动力学模拟和MM-GBSA自由能计算方法判断H1N1流感病毒D151G突变株对奥司他韦的抗药性;应用分子对接软件Autodock从ZINC数据库筛选与D151G突变神经氨酸酶结合能力较强的化合物。结果:D151G突变神经氨酸酶与奥司他韦的结合能比野生型神经氨酸酶与奥司他韦的结合能降低了-4.61kcal/mol;筛选出的5个化合物及奥司他韦与D151G突变神经氨酸酶的结合能分别为-7.56、-7.71、-7.88、-7.89、-9.09和-7.21kcal/mol。结论:H1N1流感病毒D151G突变株对奥司他韦具有抗药性,筛选出的5个化合物中,4-[1-(1-金刚烷基氧化羧基)乙氨基]-3-氨基-4-氧代-丁酸与D151G突变神经氨酸酶的结合能力最强。

Aim：To observe whether mutation D151G of H1N1 influenza virus exhibits drug resistance to oseltamivir and select compounds to which mutation D151G of H1N1 influenza virus is sensitive.Methods：Molecular dynamics simulation and MM-GBSA methods were performed to judge the resistance of mutation D151G of H1N1 influenza virus to oseltamivir;molecular docking software Autodock was applied to select some compounds from ZINC database,which had higher affinity to D151G mutated neuraminidase than oseltamivir.Results：The binding energy of D151G mutated neuraminidase to oseltamivir decreased by -4.61 kcal/mol with respect to wild-type complex.The binding energies of five compounds and oseltamivir to D151G mutated neuraminidase were -7.56,-7.71,-7.88,-7.89,-9.09 and -7.21 kcal/mol,respectively.Conclusion： Mutation D151G of H1N1 influenza virus exhibits drug resistance to oseltamivir.4-[1-（1-adamantyloxycarbonyl）ethylamino]-3-amino-4-oxo-butanoic acid has highest affinity to D151G mutated neuraminidase among five candidate compounds.