APPLICATION OF THE FREE-ENERGY PERTURBATION METHOD TO HUMAN CARBONIC-ANHYDRASE-II INHIBITORS

An analysis of the free energy perturbation (FEP) method is presented that attempts to evaluate the efficacy of the FEP method in the drug d iscovery process. To accomplish this we have evaluated whether the FEP technique can accurately predict energetic and structural quantities relating to the inhibition of human carbonic anhydrase II (HCAII) by s ulfonamides. Three well-characterized (both structurally and energetic ally) sulfonamide inhibitors of HCAII were examined in this study, 1a, 1b, and 1c. Results from FEP simulations on these compounds indicate that the FEP method can predict energetic trends reasonably well; howe ver, the FEP method was less successful in reproducing detailed struct ural data. In particular, an expected movement of His-64 when inhibito r 1c was bound did not occur. We conclude that the FEP method can be u sed to determine relative free energies of binding but cannot be relie d upon to reproduce subtle geometric changes.