Gallery of Biomolecular Simulations

AutoDocking Dinucleotides to HIV-1 Integrase

Although there are good inhibitors of HIV protease and reverse transcriptase, there are currently no effective inhibitors of integrase -- the HIV enzyme that catalyzes the 3' processing of viral cDNA, and covalently inserts that processed viral cDNA into human genomic DNA. Some compounds developed to inhibit integrase bind only to the integrase-DNA complex and not to integrase alone. [1] Thus, information concerning the atomic structure of the complex of integrase bound to DNA (especially the viral cDNA) is essential to enabling structure-based drug design efforts targeted towards the integrase core alone. To understand the binding of both viral and human DNA to HIV-1 integrase, fully flexible dinucleotides were docked onto the core domain of integrase. [2] AutoDocking identified sites on integrase where favorable interactions with nucleotides can occur, and those sites were in agreement with recently published protein fingerprinting data. By analyzing the phosphates of the docked dinucleotides, we developed a model indicating where the viral cDNA and human DNA bind to the integrase core domain. In the figure shown here, 99 AutoDocked dinucleotides are shown on the Connolly solvent-accessible surface of the integrase core domain. The active site Mg ion is shown as the yellow region of the integrase surface, and the catalytic triad is displayed in green. A total of 99 out of 109 runs docked the dinucleotides near residues known to interact with dsDNA (red and green regions), as judged by a recent protein fingerprinting study.

[1] Hazuda, D.J., P. Felock, M. Witmer, A. Wolfe, K. Stillmock, J.A. Grobler, A. Espeseth, L. Gabryelski, W.W. Schleif, C. Blau, and M.D. Miller. Inhibitors of Strand Transfer That Prevent Integration and Inhibit HIV-1 Replication in Cells. Science, 287, 646-650 (2000).

[2] Perryman, A.L. & J.A. McCammon. AutoDocking Dinucleotides to the HIV-1 Integrase Core Domain: Exploring Possible Binding Sites for Viral and Genomic DNA. J. Med. Chem., 45(26), 5624-5627 (2002).

For more information on the HIV-1 integrase work described here, please contact Alexander Perryman.

McCammon Group, UCSD (http://mccammon.ucsd.edu/)
Created by Cameron Mura on Sat Jun 7 17:55:13 PDT 2003.
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