PEPTIDE MIMETICS AS ENZYME-INHIBITORS - USE OF FREE-ENERGY PERTURBATION CALCULATIONS TO EVALUATE ISOSTERIC REPLACEMENT FOR AMIDE BONDS IN APOTENT HIV PROTEASE INHIBITOR

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