Journal of Computer-Aided Molecular Design

, Volume 14, Issue 2, pp 161–179

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

  • Amedeo Caflisch
  • Hans J. Schramm
  • Martin Karplus

DOI: 10.1023/A:1008146201260

Cite this article as:
Caflisch, A., Schramm, H.J. & Karplus, M. J Comput Aided Mol Des (2000) 14: 161. doi:10.1023/A:1008146201260


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 

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Amedeo Caflisch
    • 1
  • Hans J. Schramm
    • 2
  • Martin Karplus
    • 3
  1. 1.Department of BiochemistryUniversity of ZürichZürichSwitzerland
  2. 2.Max-Planck-Institut für BiochemieMartinsriedGermany
  3. 3.Laboratoire de Chimie Biophysique, Institut Le BelUniversité Louis PasteurStrasbourgFrance

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