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

Authors: Frecer, V.; Jedinak, A.; Tossi, A.; Berti, F.; Benedetti, F.; Romeo, D.; Miertus, S.

Source: Letters in Drug Design & Discovery, Volume 2, Number 8, December 2005 , pp. 638-646(9)

Publisher: Bentham Science Publishers

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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.

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

Document Type: Review article

DOI: http://dx.doi.org/10.2174/157018005774717307

Affiliations: 1: Cancer Research Institute,Slovak Academy of Sciences, Vlarska 7, Bratislava SK-83391, Slovakia.

Publication date: 2005-12-01

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Letters in Drug Design & Discovery publishes original letters on all areas of rational drug design and discovery including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, and structure-activity relationships. The emphasis will be on publishing quality papers very rapidly. Letters will be processed rapidly by taking full advantage of Internet technology for both the submission and review of manuscripts. The journal is essential reading to all pharmaceutical scientists involved in research in drug design and discovery.

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

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