Molecular mechanism of HIV-1 integrase-vDNA interactions and strand transfer inhibitor action : a molecular modeling perspective
Copyright © 2011 Wiley Periodicals, Inc.
| Veröffentlicht in: | Journal of computational chemistry. - 1984. - 33(2012), 5 vom: 15. Feb., Seite 527-36 |
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| Weitere Verfasser: | , |
| Format: | Online-Aufsatz |
| Sprache: | English |
| Veröffentlicht: |
2012
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| Zugriff auf das übergeordnete Werk: | Journal of computational chemistry |
| Schlagworte: | Journal Article Research Support, Non-U.S. Gov't DNA, Viral HIV Integrase EC 2.7.7.- p31 integrase protein, Human immunodeficiency virus 1 YY6481J2FF |
| Zusammenfassung: | Copyright © 2011 Wiley Periodicals, Inc. Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme for splicing a viral DNA (vDNA) replica of its genome into host cell chromosomal DNA (hDNA) and has been recently recognized as a promising therapeutic target for developing anti-AIDS agents. The interaction between HIV-1 IN and vDNA plays an important role in the integration process of the virus. However, a detailed understanding about the mechanism of this interactions as well as the action of the anti-HIV drug raltegravir (RAL, approved by FDA in 2007) targeting HIV-1 IN in the inhibition of the vDNA strand transfer is still absent. In the present work, a molecular modeling study by combining homology modeling, molecular dynamics (MD) simulations with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), and molecular mechanics Generalized-Born surface area (MM-GBSA) calculations was performed to investigate the molecular mechanism of HIV-1 IN-vDNA interactions and the inhibition action of vDNA strand transfer inhibitor (INSTI) RAL. The structural analysis showed that RAL did not influence the interaction between vDNA and HIV-1 IN, but rather targeted a special conformation of HIV-1 IN to compete with host DNA and block the function of HIV-1 IN by forcing the 3'-OH of the terminal A17 nucleotide away from the three catalytic residues (Asp64, Asp116, and Glu152) and two Mg(2+) ions. Thus, the obtained results could be helpful for understanding of the integration process of the HIV-1 virus and provide some new clues for the rational design and discovery of potential compounds that would specifically block HIV-1 virus replication |
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| Beschreibung: | Date Completed 07.05.2012 Date Revised 01.12.2018 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.22887 |