Rational design, synthesis and evaluation of new protease inhibitors against AIDS

• Research unit: EU RFP
• Project number: 98.0166

Key words (English)

computer-aided drug design; dimerization inhibitors of HIV-1 protease

Alternative project number (English)

EU project number: BMH4-CT96-0823

Research programs (English)

EU-programme: 4. Frame Research Programme - 4.2 Agriculture and agroindustry

Short description (English)

See abstract

Partners and International Organizations (English)

Coordinator: CNRS (F)

Abstract (English)

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.
A computer-based combinatorial approach was used to design dimerization inhibitors of HIV-1 PR. First, the Multiple Copy Simultaneous Search (MCSS) method was used to exhaustively sample the energetically favorable positions and orientations of functional groups in the dimerization interface.
For all of the MCSS minima an approximated binding free energy is calculated by supplementing the vacuum force field with electrostatic and nonpolar solvation contributions calculated in the continuum approximation. An advance in the present study with respect to most previous ligand design works is the use of a partially flexible protein structure for the replication of the MCSS minima with favorable binding free energy. This is important since monomeric HIV-1 PR might have a conformation different from the one in the dimer. The replication is performed with an approach based on quenched molecular dynamics with very weak harmonic constraints on the protein region close to the MCSS fragment while protein regions far from the binding site are kept fixed.

Finally, the MCSS minima are connected by the Computational Combinatorial Ligand Design (CCLD) program which allows the fast and automatic generation of diverse candidate ligands.

A number of modified C-terminal peptides designed with the help of the MCSS/CCLD approach have most of their functional groups in common with known inhibitors of dimerization of HIV-1 PR.
Moreover a series of N-substituted 2,5-diketopiperazines are predicted to be potential dimerization inhibitors of HIV-1 PR. They could be synthesized by combinatorial chemistry.

The results of this study have been published in
A. Caflisch et al., Journal of Computer-Aided Molecular Design 14, 161-179, 2000.

References in databases (English)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
Hallwylstrasse 4
CH-3003 Berne, Switzerland
Tel. [phone]
Swiss Project-Number: 98.0166