In Silico Analysis Revealed a Unique Binding but Ineffective Mode of Amantadine to Influenza Virus B M2 Channel.
In Silico Analysis Revealed a Unique Binding but Ineffective Mode of Amantadine to Influenza Virus B M2 Channel.
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DOI：
10.1021/acs.jpclett.0c03560
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发表时间：
2021-01
期刊：
影响因子：
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通讯作者：
Yue Zhang;Qingchuan Zheng
中科院分区：
文献类型：
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作者：
Yue Zhang;Qingchuan Zheng
甲型流感病毒（AM2）和B型流感病毒（BM 2）的M2质子通道具有高度保守的功能基序，被认为是有效靶点。目前还没有针对BM2的有效药物。研究表明，AM2通道阻断剂金刚烷胺（amantadine，AMT）能与BM 2通道结合，但AMT对BM 2通道缺乏抑制作用。然而，AMT与BM 2结合但无效模式的研究具有挑战性。为了解决这一难题并为靶向BM 2抑制剂的药物设计提供更多信息，进行了多个分子动力学模拟。我们发现AMT在BM 2中主要采用上结合模式，参与了从下模式到上模式的转换翻转。此外，我们发现了一个新的关键因素来解释AMT对BM 2的无效抑制，因为AMT和BM 2之间的空间几何形状不匹配。本研究丰富了BM2的结构特征信息，为合理设计抗流感病毒B的药物提供了新的视角。
The M2 proton channel of influenza A (AM2) and B (BM2) have a highly conserved function motif, considered as the effective target. As yet, there is no effective drug against BM2. Research showed that AM2 channel blocker, amantadine (AMT), was able to bind to BM2 channel, but AMT lacked inhibition against BM2. Nevertheless, the study of the binding but ineffective mode of AMT to BM2 is challenging. To resolve the challenge and obtain more information for drug design of inhibitors targeting BM2, multiple molecular dynamics simulations were performed. We discovered AMT mainly adopted up binding mode in BM2, involved in a transition flipping from down mode to up mode. Furthermore, we discovered a new key factor to explain ineffective inhibition of AMT to BM2 because of the unmatched spatial geometry between AMT and BM2. Our work could enrich structural feature information on BM2 and provide a new perspective for rational drug design of anti-influenza B.