Journal of Computer-Aided Molecular Design

, Volume 14, Issue 2, pp 161-179

First online:

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

  • Amedeo CaflischAffiliated withDepartment of Biochemistry, University of Zürich
  • , Hans J. SchrammAffiliated withMax-Planck-Institut für Biochemie
  • , Martin KarplusAffiliated withLaboratoire de Chimie Biophysique, Institut Le Bel, Université Louis Pasteur

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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.

de novo design finite-difference Poisson–Boltzmann HIV-1 aspartic proteinase inhibitors of dimerization MCSS structure-based drug design