Influenza epidemics are responsible for an average of 3-5 millions of severe cases and up to 500,000 deaths around the world. One of flu pandemic types is influenza A(H1N1)pdm09 virus (pdm09H1N1). Oseltamivir is the antiviral drug used to treat influenza targeting at neuraminidase (NA) located on the viral surface. Influenza virus undergoes high mutation rates and leads to drug resistance, and thus the development of more efficient drugs is required. In the present study, all-atom molecular dynamics simulations were applied to understand the oseltamivir resistance caused by the single E119D and double E119D/H274Y mutations on NA. The obtained results in terms of binding free energy and intermolecular interactions in the ligand-protein interface showed that the oseltamivir could not be well accommodated in the binding pocket of both NA mutants and the 150-loop moves out from oseltamivir as an "open" state. A greater number of water molecules accessible to the binding pocket could disrupt the oseltamivir binding with NA target as seen be high mobility of oseltamivir at the active site. Additionally, our finding could guide to the design and development of novel NA inhibitor drugs.

中文翻译：

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pdm09H1N1流感神经氨酸酶中​​单一E119D和双重E119D / H274Y突变引起的奥司他韦耐药性来源。

流行性感冒在世界范围内平均造成3-5百万例严重病例，并导致多达500,000例死亡。流感大流行类型之一是A型流感（H1N1）pdm09病毒（pdm09H1N1）。Oseltamivir是一种抗病毒药，用于治疗针对病毒表面神经氨酸酶（NA）的流感。流感病毒经历高突变率并导致耐药性，因此需要开发更有效的药物。在本研究中，使用全原子分子动力学模拟来了解由NA上的单个E119D和两个E119D / H274Y突变引起的奥司他韦耐药性。就结合自由能和配体-蛋白质界面中的分子间相互作用而言，所获得的结果表明，奥司他韦不能很好地容纳在两个NA突变体的结合口袋中，并且150个环从奥司他韦中移出为“开放”状态。 。从活性位点上的奥司他韦的高迁移率可以看出，结合口袋中可及的大量水分子可能会破坏奥司他韦与NA靶的结合。此外，我们的发现可以指导新型NA抑制剂药物的设计和开发。