Design of peptidomimetic inhibitors of aspartic protease of HIV-1 containing -Phe Psi Pro- core and displaying favourable ADME-related properties

Aspartic protease (PR) of HIV-1 virus represents a valid therapeutic target for the design of antiviral agents suitable for treatment of AIDS. We have designed peptidomimetic PR inhibitors containing a novel dihydroxyethylenediamine -Phe-PsiCHOH-CHOH]-Pro- core using molecular modelling approach that predicts the inhibitory potencies (IC(50)(pre)) in terms of computed relative enzyme-inhibitor complexation Gibbs free energies (Delta Delta G(comp)). The modelling approach considers not only the enzyme-inhibitor interactions, but includes also the solvent and entropic effects affecting the enzyme inhibition. The objectives of this study were to optimize the number and type of flanking residues that occupy the S(3), S(2) and S(2'), S(3') positions in the PR binding pocket and to select potent lead candidates, which display also favourable ADME-related properties. The structure-based design was combined with a synthetic strategy used to prepare a training set of 10 analogues sharing the -Phe Psi Pro- core. This strategy couples stereochemical control with full flexibility in the choice of the flanking residues and in vitro activity assays. A QSAR model correlating calculated Delta Delta G(comp) with the measured IC(50)(exp) values for the training set was prepared and confirmed that our computational approach can serve for reliable prediction of PR inhibitory potencies of peptidomimetics. The appropriate choice of the flanking residues allowed us to design virtual lead compounds, such as FP14, FP23 and FP76, with reduced molecular weight, predicted inhibitory potencies in the picomolar range, promising ADME profiles and a potential to escape drug resistance due to favourable interactions with the PR backbone.