A protoporphyrin IX-based model for cytochrome P-450 iron-binding inhibitors: SAM1 calculations of structure and complexation enthalpy

Abstract

A methyl diester protoporphyrin IX complex with ferric ion in a low-spin doublet state and with ethyl sulfide as a constant axial ligand, is proposed as a model system for examining cytochrome P-450 Fe-binding inhibitors, e.g., imidazoles and pyridines, which can coordinate as a second axial ligand. The SAM1 semiempirical method was used to calculate optimized structures and complexation enthalpies for a variety of organic ligands, as well as for the resting state aquo complex, under the assumption that such inhibitors are stronger Fe ligands than a water molecule in the enzyme's resting state and thereby block the P-450 catalytic cycle. The SAM1 structures agree qualitatively with X-ray structures of P-450cam with bound ligands, and are in reasonable agreement regarding details such as Fe-ligand bond lengths. The enthalpy results and structures provide insights into how the inhibitory potency of imidazoles is decreased by substituents around the divalent nitrogen. In particular, a substituted imidazole may still intrinsically be able to bind to the resting state iron but with a lowered binding energy, so that it is thermodynamically unable to displace the bound water molecule. Qualitative predictions based on SAM1 binding enthalpies are in accord with experimental structural and inhibitory data. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem 88: 147–153, 2002