Structure Based Design of Inhibitors of Aspartic Protease of HIV-1

Title: Structure Based Design of Inhibitors of Aspartic Protease of HIV-1

Volume: 2 Issue: 8

Author(s): V. Frecer, A. Jedinak, A. Tossi, F. Berti, F. Benedetti, D. Romeo and S. Miertus

Affiliation:

Keywords: Aspartic protease of HIV-1, peptidomimetic inhibitors, structure based design, QSAR, ADME prediction

Abstract: The aspartic protease of HIV-1 represents a valid therapeutic target of antiviral agents suitable for the treatment of AIDS. We have designed peptidomimetic inhibitors for this enzyme with a hydroxyethylenediamine core, based on a molecular modeling approach that predicts the effectiveness of the designed compounds in terms of computed enzyme-inhibitor complexation Gibbs free energies. This structurebased molecular design was then combined with a synthetic strategy that couples stereochemical control with full flexibility in the choice of the central core side chains and of the flanking residues. A series of peptidomimetic inhibitors was thus assembled from readily available amino acids and carboxylic acids and -Phe-ψ[CH2-(r/s)CHOH]-Phe- cores. The IC50 values for these compounds ranged from 3 nM to 80 μM, allowing a QSAR analysis and identification of factors that determine the inhibition potency of the compounds. Predicted ADME-related properties of the inhibitor candidates span a range of pharmacokinetics profiles, which allows selection of a potent and bioavailable lead compound for further development.

Cite this article as:

Frecer V., Jedinak A., Tossi A., Berti F., Benedetti F., Romeo D. and Miertus S., Structure Based Design of Inhibitors of Aspartic Protease of HIV-1, Letters in Drug Design & Discovery 2005; 2 (8) . https://dx.doi.org/10.2174/157018005774717307