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. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011