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-C[CHOH–CHOH]-Pro– core using molecular modelling approach that
predicts the inhibitory potencies (ICpre
50 ) in terms of computed relative enzyme–inhibitor complexation
Gibbs free energies (DDGcomp). 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 S3, S2
and S20, S30 positions in the PR binding pocket and to select potent lead candidates, which display also
favourable ADME-related properties. The structure-based designwas combined with a synthetic strategy
used to prepare a training set of 10 analogues sharing the –PheCPro– 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 DDGcomp with the measured ICexp
50 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.
