title: Molecular mechanism of HIV-1 integrase-vDNA interactions and strand transfer inhibitor action: a molecular modeling perspective.
abstract: 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.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Xue
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Liu
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yao
mesh_terms: D004279:DNA, Viral / Q000737:chemistry*; D019427:HIV Integrase / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation
chemical_list: D004279:DNA, Viral; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1