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A. Caflisch; H.J. Schramm; M. Karplus

Journal: J. Comput. Aided Mol. Des.
Year: 2000
Volume: 14
Issue: 2
Pages: 161-179
DOI: 10.1023/A:1008146201260
Type of Publication: Journal Article

Aspartic Acid Endopeptidases; Combinatorial Chemistry Techniques; Computer-Aided Design; Dimerization; HIV-1; Models, Molecular; Protease Inhibitors


Inhibition of dimerization to the active form of the HIV-1 aspartic proteinase (HIV-1 PR) may be a way to decrease the probability of escape mutations for this viral protein. The Multiple Copy Simultaneous Search (MCSS) methodology was used to generate functionality maps for the dimerization interface of HIV-1 PR. The positions of the MCSS minima of 19 organic fragments, once postprocessed to take into account solvation effects, are in good agreement with experimental data on peptides that bind to the interface. The MCSS minima combined with an approach for computational combinatorial ligand design yielded a set of modified HIV-1 PR C-terminal peptides that are similar to known nanomolar inhibitors of HIV-1 PR dimerization. A number of N-substituted 2,5-diketopiperazines are predicted to be potential dimerization inhibitors of HIV-1 PR.