Peptide mimetics as enzyme inhibitors: use of free energy perturbation calculations to evaluate isosteric replacement for amide bonds in a potent HIV protease inhibitor.

We present the application of free energy perturbation theory/molecular dynamics to predict the consequence of replacing each of the seven peptide bonds in the potent HIV protease inhibitor JG365: ACE (acetyl)-Ser-Leu-Asn-HEA (hydroxyethylamine analog of Phe-Pro)-Ile-Val-NME (N-methyl) by ethylene or fluoroethylene isosteres. Replacing two of these bonds may well lead to significantly tighter binding; replacing two others is predicted to significantly diminish the binding affinity. Also, for three of the peptide bonds fluoroethylene replacements could lead to increased binding of free energies of the inhibitors. Our results should be considered as predictive since there are, as yet, no experimental results on such peptide replacements as enzyme inhibitors.