Understanding the effect of drug-resistant mutations of HIV-1 intasome on raltegravir action through molecular modeling study
文献类型：期刊论文
| 作者 | Xue, Weiwei1; Qi, Ji2 ; Yang, Ying1; Jin, Xiaojie1; Liu, Huanxiang3; Yao, Xiaojun1,4
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| 刊名 | MOLECULAR BIOSYSTEMS
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| 出版日期 | 2012 |
| 卷号 | 8页码:2135-2144 |
| ISSN号 | 1742-206X |
| DOI | 10.1039/c2mb25114k |
| 文献子类 | Article |
| 英文摘要 | Raltegravir is the first FDA-approved drug targeting the strand transfer step of HIV-1 integration. However, the rapid emergence of viral strains that are highly resistant to raltegravir has become a critical problem. Unfortunately, the detailed molecular mechanism of how HIV-1 integrase (IN) mutations actually confer drug resistance is not well understood. In the present study, starting from our previously constructed complex of HIV-1 IN and viral DNA, we employed molecular dynamics (MD) simulation and molecular mechanics generalized Born surface area (MM-GBSA) calculation, to uncover the molecular mechanism behind the resistant mechanism of HIV-1 IN to raltegravir. The values of the calculated binding free energy follow consistently the experimentally observed ranking of resistance levels. A detailed analysis of the results of MD simulation suggests that the Tyr143 located in the 140s loop (e. g., residues from Gly140 to Gly149) is a key anchoring residue that leads to stable raltegravir binding. The decrease in the interaction at this residue is one of the key reasons responsible for the resistance of HIV-1 IN to raltegravir. Additionally, the calculation results also proved that the 3' adenosine flip in different conformations in the wild-type and mutant HIV-1 IN-viral DNA complexes play an important role in raltegravir binding. Our results could provide a structural and energetic understanding of the raltegravir-resistant mechanism at the atomic level and provide some new clues on how to design new drugs that may circumvent the known resistance mutations. |
| WOS关键词 | IMMUNODEFICIENCY-VIRUS TYPE-1 ; FREE-ENERGY CALCULATIONS ; INTEGRASE INHIBITORS ; STRAND TRANSFER ; IN-VITRO ; DYNAMICS SIMULATIONS ; RESP METHODOLOGY ; SOLVENT MODELS ; FORCE-FIELD ; BINDING |
| 资助项目 | Fundamental Research Funds for the Central Universities[lzujbky-2011-19] ; Fundamental Research Funds for the Central Universities[lzujbky-2012-k10] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| 出版者 | ROYAL SOC CHEMISTRY |
| WOS记录号 | WOS:000305965100012 |
| 源URL | [http://119.78.100.186/handle/113462/47749]  |
| 专题 | 中国科学院近代物理研究所 |
| 通讯作者 | Yao, Xiaojun |
| 作者单位 | 1.Lanzhou Univ, Dept Chem, State Key Lab Appl Organ Chem, Lanzhou 730000, Peoples R China 2.Chinese Acad Sci, Inst Modern Phys, Lanzhou 730000, Peoples R China 3.Lanzhou Univ, Sch Pharm, Lanzhou 730000, Peoples R China 4.Lanzhou Univ, Key Lab Preclin Study New Drugs Gansu Prov, Lanzhou 730000, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xue, Weiwei,Qi, Ji,Yang, Ying,et al. Understanding the effect of drug-resistant mutations of HIV-1 intasome on raltegravir action through molecular modeling study[J]. MOLECULAR BIOSYSTEMS,2012,8:2135-2144. |
| APA | Xue, Weiwei,Qi, Ji,Yang, Ying,Jin, Xiaojie,Liu, Huanxiang,&Yao, Xiaojun.(2012).Understanding the effect of drug-resistant mutations of HIV-1 intasome on raltegravir action through molecular modeling study.MOLECULAR BIOSYSTEMS,8,2135-2144. |
| MLA | Xue, Weiwei,et al."Understanding the effect of drug-resistant mutations of HIV-1 intasome on raltegravir action through molecular modeling study".MOLECULAR BIOSYSTEMS 8(2012):2135-2144. |
入库方式： OAI收割
来源：近代物理研究所
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