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

Examining structural analogs of elvitegravir as potential inhibitors of HIV-1 integrase 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Virology Springer Journals

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

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Publisher
Springer Vienna
Copyright
Copyright © 2014 by Springer-Verlag Wien
Subject
Biomedicine; Virology; Medical Microbiology; Infectious Diseases
ISSN
0304-8608
eISSN
1432-8798
D.O.I.
10.1007/s00705-014-2038-y
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

Archives of VirologySpringer Journals

Published: Aug 1, 2014

References

  • Comparative studies on inhibitors of HIV protease: A target for drug design
    Jayaraman, S; Shah, K
  • Crystal structures of the catalytic domain of HIV-1 integrase free and complexed with its metal cofactor: high level of similarity of the active site with other viral integrases
    Maignan, S; Guilloteau, JP; Zhou-Liu, Q; Clément-Mella, C; Mikol, V
  • Structure of a two-domain fragment of HIV-1 integrase: implications for domain organization in the intact protein
    Wang, J-Y; Ling, H; Yang, W; Craigie, R
  • Crystal structure of an active two domain derivative of Rous sarcoma virus integrase
    Yang, Z-N; Mueser, TC; Bushman, FD; Hyde, CC
  • HIV-1 subtypes and recombinants in the Republic of Congo
    Niama, FR; Toure-Kane, C; Vidal, N; Obengui, P; Bikandou, B; Ndoundou Nkodia, MY; Montavon, C; Diop-Ndiaye, H; Mombouli, JV; Mokondzimobe, E; Diallo, AG; Delaporte, E; Parra, HJ; Peeters, M; Mboup, S

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