COMPARATIVE-STUDY OF FREE-ENERGIES OF SOLVATION OF PHENYLIMIDAZOLE INHIBITORS OF CYTOCHROME P450CAM BY FREE-ENERGY SIMULATION, AMSOL, AND POISSON-BOLTZMANN METHODS

Free energies of solvation of phenylimidazole inhibitors of cytochrome P450 cam were determined using (1) free energy simulation, (2) AMSOL- SM2 semiempirical methods, and (3) Poisson-Boltzmann methods. The goal s of this study were threefold: (1) to compare the results obtained fr om the three different methods, (2) to investigate the effect of inclu sion of intraperturbed group interactions on free energy simulation es timates of solvation free energy differences, and (3) to investigate t o what extent differences in free energies of solvation among three of these inhibitors could account for observed differences in their enzy me binding free energies. In general, relative solvation free energies obtained from the free energy simulations and AMSOL-SM2 methods give comparable results (i.e., the same rank ordering and similar quantitat ive results, differing significantly from results obtained using Poiss on-Boltzmann methods). The free energy simulation studies suggest that the neglect of intrapertubed group interactions had little effect on rank order of free energies of solvation of the polar phenylimidazoles . The relative desolvation free energies of the three inhibitors of P4 50 cam-1-phenylimidazole (1-PI), 2-phenylimidazole (2-PI), and 4-pheny limidazole (4-PI)-with known enzyme bound X-ray structures parallel th at of their known binding affinities and could account for most of the differences in the free energies of binding of these three inhibitors to P450 cam. The origin of the difference of the free energies of sol ution of these three inhibitors is primarily the additional interactio n between solvent and N-H group in the imidazole ring of 2- and 4-phen ylimidazole that is absent in the 1-phenylimidazole isomer. This hypot hesis is substantiated by a second comparison of the relative solvatio n free energies of 4-phenylimidazole with its methylated derivative, 3 -methyl-4-phenylimidazole, also lacking an N-H group. (C) 1996 by John Wiley & Sons, Inc.