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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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

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

Volume 2, Issue 8, 2005

Page: [638 - 646] Pages: 9

DOI: 10.2174/157018005774717307

Price: $65


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.

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

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