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How does Darunavir prevent HIV-1 protease dimerization?

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D. Huang; A. Caflisch

Journal: J. Chem. Theory Comput.
Year: 2012
Volume: 8
Issue: 5
Pages: 1786-1794
DOI: 10.1021/ct300032r
Type of Publication: Journal Article

AIDS; AMBER; CHARMM; Darunavir; Dimerization; HIV Protease; inhibition; molecular dynamics simulations; small molecule binding


The drug Darunavir (DRV) is a potent inhibitor of HIV-1 protease (PR), a homodimeric essential enzyme of the AIDS virus. Recent experimental data suggest that DRV is able to prevent dimerization of HIV-1 PR, which, together with its high affinity for the mature enzyme, has been linked to the high genetic barrier to the development of viral resistance. The mechanism of dimerization inhibition and the binding mode(s) of DRV to monomeric HIV-1 PR are unknown. Here, multiple molecular dynamics simulations with explicit solvent (for a total of 11 μs with the CHARMM force field and 1 μs with the Amber force field) show that the monomer of HIV-1 PR is structurally stable and reveal a major binding mode of DRV. This binding mode is stabilized by favorable interactions between the apolar groups of DRV and the hydrophobic residues Ile32, Ile47, Ile50, Ile54, Pro79, Val82, and Ile84. The binding mode to monomeric HIV-1 PR identified by molecular dynamics is different from the two binding modes observed in the crystal structure of the complex with dimeric HIV-1 PR. As an example, there are no interactions between DRV and the catalytic Asp25 in the binding mode to monomeric HIV-1 PR revelead by the simulations. In contrast, the simulations show extensive and stable interactions between DRV and the flap (residues 46–55), which are likely to sterically hinder the formation of the flap interface as observed in the dimeric structure. Which of the two mechanisms of inhibition (dimerization inhibition by association with the flap or binding to the active site of the mature enzyme) dominates might depend on the HIV-1 PR mutations, and it is likely that dimerization inhibition is predominant for multiple mutations at the active site in multidrug resistant strains.