TY - JOUR KW - Models, Molecular KW - Aspartic Acid Endopeptidases KW - HIV-1 KW - Protease Inhibitors KW - Dimerization KW - Computer-Aided Design KW - Combinatorial Chemistry Techniques AU - A. Caflisch AU - H. J. Schramm AU - M. Karplus AB -

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.

BT - Journal of Computer-Aided Molecular Design C1 - 0023 DA - 2000 Feb DO - 10.1023/A:1008146201260 IS - 2 J2 - J. Comput. Aided Mol. Des. LA - eng M3 - Research Article N2 -

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.

PY - 2000 SP - 161 EP - 179 T2 - Journal of Computer-Aided Molecular Design TI - Design of dimerization inhibitors of HIV-1 aspartic proteinase: A computer-based combinatorial approach VL - 14 SN - 0920-654X ER -