Molecular design of fluorine-containing peptide mimetics

The free energy perturbation (FEP) and free energy derivatives (FED) methodology with molecular dynamics simulations has been applied to study possible improvement of the inhibition properties of the JG-365 inhibitor toward HIV aspartic protease. Our study concerns the assessment of the effect of replacement of some peptide bonds in JG-365 by trans-ethylenic or fluoroethylenic units. According to our free energy perturbation simulations such replacement could be beneficial for two of those peptide bonds but not for the others. The results of application of the free energy derivative technique confirms the FEP results and also suggest other possible modification of the JG-365 inhibitor which could lead to increased potency. Our results are only predictive in nature, since the proposed pseudopeptidic inhibitors have not yet been synthesized.