Examining structural analogs of elvitegravir as potential inhibitors of HIV-1 integrase

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• 作者：Kavita Shah (1)
  Saumya Gupta (2)
  Hirdyesh Mishra (3)
  Prashant K. Sharma (1)
  Amit Jayaswal (2)
  
• 刊名：Archives of Virology
• 出版年：2014
• 出版时间：August 2014
• 年：2014
• 卷：159
• 期：8
• 页码：2069-2080
• 全文大小：3,149 KB
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• 作者单位：Kavita Shah (1)
  Saumya Gupta (2)
  Hirdyesh Mishra (3)
  Prashant K. Sharma (1)
  Amit Jayaswal (2)
  
  1. Department of Environment and Sustainable Sciences, Institute of Environment and Sustainable Development, Banaras Hindu University, Varanasi, 221005, India
  2. Department of Bioinformatics, MMV, Banaras Hindu University, Varanasi, 221005, India
  3. Department of Physics, MMV, Banaras Hindu University, Varanasi, 221005, India
  
• ISSN：1432-8798

文摘

Acquired immunodeficiency syndrome (AIDS) is a major health problem in many parts of the world. The human immunodeficiency virus-1 integrase (HIV-1 IN) enzyme has been targeted in HIV patients for therapy. Several integrase inhibitors have been reported, but only elvitegravir (EVG), a new-generation drug, is clinically approved for HIV treatment. In the present work, we investigated two structural analogs of EVG as potential inhibitors of the target molecule, HIV-1 IN. The ligand binding site on HIV-1 IN was identified using Q-SiteFinder, and the HIV-1 IN protein was docked with ligand (EVG and/or analogs) using AutoDock 4. The results suggest that Lys173, Thr125, and His171 are involved in enzyme-substrate binding through hydrogen bonds. Single mutations carried out at Lys173, viz. Lys173Leu (polar?>?nonpolar) and Lys173Gln (polar?>?polar), in chain B using PyMOL showed the mutants to have lower binding energy when docked with analog 2, suggesting it to be more stable than analog 1. In conclusion, the mutant HIV-1 IN can bind EVG and its analogs. The physicochemical and pharmacokinetic parameters also show analog 2 to be a promising molecule that can be developed as an alternative to EVG to help overcome the problem of drug resistance by HIV to this inhibitor. Analog 2 may be used as an HIV-1 IN inhibitor with similar potential to that of EVG. Further validation through wet-lab studies, however, is required for future applications.