Design of dimerization inhibitors of HIV-1 aspartic proteinase: A computer-based combinatorial approach

Inhibition of dimerization to the active form of the HIV-1 aspartic protein ase (HIV-1 PR) may be a way to decrease the probability of escape mutations for this viral protein. The Multiple Copy Simultaneous Search (MCSS) metho dology was used to generate functionality maps for the dimerization interfa ce of HIV-1 PR. The positions of the MCSS minima of 19 organic fragments, o nce postprocessed to take into account solvation effects, are in good agree ment with experimental data on peptides that bind to the interface. The MCS S minima combined with an approach for computational combinatorial ligand d esign yielded a set of modified HIV-1 PR C-terminal peptides that are simil ar to known nanomolar inhibitors of HIV-1 PR dimerization. A number of N-su bstituted 2,5-diketopiperazines are predicted to be potential dimerization inhibitors of HIV-1 PR.