Abstract

Influenza A virus is capable of rapidly infecting large human populations, warranting the development of novel drugs to efficiently inhibit virus replication. A transmembrane ion channel formed by the M2 protein plays an important role in influenza virus replication. A reasonable approach to designing an effective antivirus drug is constructing a molecule that binds in the M2 transmembrane proton channel, blocks H⁺ proton diffusion through the channel, and thus the influenza A virus cycle. The known anti-influenza drugs amantadine and rimantadine have a weak effect on influenza A virus replication. A new class of positively charged molecules, diazabicyclooctane derivatives with a constant charge of +2, was proposed to block proton diffusion through the M2 ion channel. Molecular dynamics simulations were performed to study the temperature fluctuations in the M2 structure, and ionization states of histidine residues were established at physiological pH values. Two types of diazabicyclooctane derivatives were analyzed for binding with the M2 ion channel. An optimal structure was determined for a blocker to most efficiently bind with the M2 ion channel and block proton diffusion. The new molecule is advantageous over amantadine and rimantadine in having a positive charge of +2, which creates a positive electrostatic potential barrier to proton transport through the M2 ion channel in addition to a steric barrier.

中文翻译：

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一种有效的甲型流感病毒M2离子通道抑制剂的设计

摘要

甲型流感病毒能够迅速感染大量人口，因此有必要开发能有效抑制病毒复制的新型药物。由M2蛋白形成的跨膜离子通道在流感病毒复制中起重要作用。设计有效抗病毒药物的合理方法是构建结合在M2跨膜质子通道中的分子，阻断H ⁺质子通过通道扩散，从而导致甲型流感病毒循环。已知的抗流感药物金刚烷胺和金刚乙胺对甲型流感病毒的复制作用较弱。有人提出了一种新型的带正电荷的分子，具有恒定电荷+2的二氮杂双环辛烷衍生物，以阻止质子通过M2离子通道扩散。进行分子动力学模拟以研究M2结构中的温度波动，并在生理pH值下建立组氨酸残基的电离状态。分析了两种类型的二氮杂双环辛烷衍生物与M2离子通道的结合。确定了最佳的结构，以使阻断剂最有效地与M2离子通道结合并阻断质子扩散。