How Does Influenza Virus A Escape from Amantadine?
文献类型：期刊论文
| 作者 | Qin, Guangrong1; Yu, Kunqian1 ; Shi, Ting1; Luo, Cheng1; Li, Guohui2; Zhu, Weiliang1,3; Jiang, Hualiang1,3
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| 刊名 | JOURNAL OF PHYSICAL CHEMISTRY B
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| 出版日期 | 2010-07-01 |
| 卷号 | 114期号:25页码:8487-8493 |
| ISSN号 | 1520-6106 |
| DOI | 10.1021/jp911588y |
| 文献子类 | Article |
| 英文摘要 | Antiflu drugs such as amantadine (AMT) were reported to be insensitive to influenza A virus gradually after their marketing. Mutation experiments indicate that the trans-membrane domain of M2 protein plays an essential role in AMT resistance, especially the S31N mutation. To investigate the details of structure and mechanism, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations have been carried out on both the wild-type protein and its S31N mutant. Our MD simulations reveal AMT can occupy different binding positions in the pore of M2 channel, and the binding modes have also been verified and analyzed by QM/MM calculations. More importantly, we find the formation of a water wire modulated by the binding position of AMT to be essential for the function of M2 protein, and, the block of water wire can inhibit channel function in the WT system. Failure of channel blocking would cause AMT drug resistance in the S31N mutant. These results support one of the conflicting views about M2 drug binding sites: AMT binds to the pore of M2 channel. Our findings help clarify the resistant mechanism of AMT to M2 protein and should facilitate the discovery of new drugs for treating influenza A virus. |
| WOS关键词 | M2 PROTON CHANNEL ; A VIRUS ; DRUG-INHIBITION ; ION-CHANNEL ; MECHANISM ; ONIOM ; GEOMETRY ; PROTEIN ; MODEL ; OPTIMIZATION |
| 资助项目 | State Key Program of Basic Research of China[2009CB918502] ; Hi-Tech Research and Development Program of China[2006AA01A124] ; Hi-Tech Research and Development Program of China[2009AA01A137] ; National ST Major Project[2009ZX09301-001] ; National ST Major Project[2009ZX09501-001] ; Shanghai Committee of Science and Technology[08JC1401600] ; National Natural Science Foundation of China[20721003] ; National Natural Science Foundation of China[20720102040] ; National Natural Science Foundation of China[20702009] ; Chinese Academy of Sciences[INFO-115-B01] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000278982200024 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278861]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Yu, Kunqian |
| 作者单位 | 1.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Mol Modeling & Design, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China; 3.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China |
| 推荐引用方式 GB/T 7714 | Qin, Guangrong,Yu, Kunqian,Shi, Ting,et al. How Does Influenza Virus A Escape from Amantadine?[J]. JOURNAL OF PHYSICAL CHEMISTRY B,2010,114(25):8487-8493. |
| APA | Qin, Guangrong.,Yu, Kunqian.,Shi, Ting.,Luo, Cheng.,Li, Guohui.,...&Jiang, Hualiang.(2010).How Does Influenza Virus A Escape from Amantadine?.JOURNAL OF PHYSICAL CHEMISTRY B,114(25),8487-8493. |
| MLA | Qin, Guangrong,et al."How Does Influenza Virus A Escape from Amantadine?".JOURNAL OF PHYSICAL CHEMISTRY B 114.25(2010):8487-8493. |
入库方式： OAI收割
来源：上海药物研究所
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