Molecular dynamics simulation studies of the wild type and E92Q/N155H mutant of Elvitegravir-resistance HIV-1 integrase

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• 作者：Qi Chen (1)
  Xiaolin Cheng (2) (3)
  Dongqing Wei (1)
  Qin Xu (1)
  
  1. State Key Laboratory of Microbial Metabolism and College of Life Science and Biotechnology ; Shanghai Jiao Tong University ; Shanghai ; 200240 ; China
  2. UT/ORNL Center for Molecular Biophysics ; Oak Ridge National Laboratory ; Oak Ridge ; Tennessee ; 37831 ; USA
  3. Department of Biochemistry and Cellular and Molecular Biology ; University of Tennessee ; Knoxville ; Tennessee ; 37996 ; USA
  
• 关键词：HIV ; 1 integrase ; elvitegravir ; molecular dynamics simulation ; drug resistance
• 刊名：Interdisciplinary Sciences: Computational Life Sciences
• 出版年：2015
• 出版时间：March 2015
• 年：2015
• 卷：7
• 期：1
• 页码：36-42
• 全文大小：771 KB
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• 刊物主题：Computer Appl. in Life Sciences; Computational Biology/Bioinformatics; Statistics for Life Sciences, Medicine, Health Sciences; Theoretical and Computational Chemistry; Theoretical, Mathematical and Computational Physics; Computational Science and Engineering;
• 出版者：International Association of Scientists in the Interdisciplinary Areas
• ISSN：1867-1462

文摘

Although Elvitegravir (EVG) is a newly developed antiretrovirals drug to treat the acquired immunodeficiency syndrome (AIDS), drug resistance has already been found in clinic, such as E92Q/N155H and Q148H/G140S. Several structural investigations have already been reported to reveal the molecular mechanism of the drug resistance. As full length crystal structure for HIV-1 integrase is still unsolved, we herein use the crystal structure of the full length prototype foamy virus (PFV) in complex with virus DNA and inhibitor Elvitegravir as a template to construct the wild type and E92Q/N155H mutant system of HIV-1 integrase. Molecular dynamic simulations was used to revel the binding mode and the drug resistance of the EVG ligand in E92Q/N155H. Several important interactions were discovered between the mutated residues and the residues in the active site of the E92Q/N155H double mutant pattern, and cross correlation and clustering methods were used for detailed analysis. The results from the MD simulation studies will be used to guide the experimental efforts of developing novel inhibitors against drug-resistant HIV integrase mutants.