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Artif Intell Med. 2009 Feb-Mar;45(2-3):197-206. doi: 10.1016/j.artmed.2008.08.011. Epub 2008 Oct 15.

Computational proteomics analysis of binding mechanisms and molecular signatures of the HIV-1 protease drugs.

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Department of Pharmaceutical Chemistry, School of Pharmacy and Center for Bioinformatics, The University of Kansas, 2030 Becker Drive, Lawrence, KS 66047, USA.



Computational proteomics analysis of biomolecular interactions is proposed to determine molecular signatures of the HIV-1 protease inhibitors. A comparative microscopic analysis is conducted for a panel of inhibitors which exemplify a diversity of the HIV-1 PR binding mechanisms, from the active site inhibition to intervening with the protease folding and dimerization.


Replica-exchange Monte Carlo simulations with the conformational ensembles of the HIV-1 PR dimer and monomer structures enable a molecular analysis underlying diversity of the HIV-1 PR binding mechanisms.


We have investigated the molecular basis underlying diversity of the HIV-1 PR binding mechanisms. The molecular basis of the HIV-1 PR active site and dimerization inhibition mechanisms has been analyzed for an active site tripeptide inhibitor and a tetrapeptide inhibitor, which can act as both a dimerization inhibitor and a competitive active site inhibitor. We have also simulated a structural mimicry mechanism of the HIV-1 PR folding inhibition and dimerization, according to which the folding inhibitor targets the conserved HIV-1 PR regions by mimicking the interaction network of the active dimer.


We have shown that binding interfaces of the studied dimerization and folding HIV-1 PR inhibitors may enable structural mimicry with the hot spot residues of the HIV-1 PR dimer. The proposed structural models of intervening with the HIV-1 PR dimerization and folding support the mechanism of structural mimicry, which may alleviate drug resistance effects.

[Indexed for MEDLINE]

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