Predicting Activation Enthalpies of Cytochrome-P450-Mediated Hydrogen Abstractions. 2. Comparison of Semiempirical PM3, SAM1, and AM1 with a Density Functional Theory Method

Abstract

Predicting the biotransformation of xenobiotics is important in the chemical and pharmaceutical industries, as well as in toxicology. Here, we extend and evaluate the rapid methodology of Korzekwa, Jones, and Gillette (J. Am. Chem. Soc. 1990, 112, 7042-7046 ) to estimate the activation enthalpy (DeltaH) of hydrogen-abstraction by cytochrome P450 (CYP) enzymes, using the p-nitrosophenoxy radical (PNPO) as a simple surrogate for the CYP active oxygen species. The DeltaH is estimated with a linear regression model using the reaction enthalpy and ionization energy (of the substrate radical) as predictor variables, calculated by semiempirical (SE) methods. While Korzekwa et al. used the SE method AM1, we applied PM3 and SAM1 and compared the results of the three methods. For 24 substrates, the AM1-, PM3-, and SAM1-derived regression models showed R(2) values of 0.89, 0.90, and 0.93, respectively, for the correlation between calculated and predicted DeltaH. Furthermore, we compared the DeltaH() calculated semiempirically using PNPO radical with density functional theory (DFT) B3LYP activation energies calculated by Olsen et al. (J. Med. Chem. 2006, 49, 6489-6499 ) using a more realistic iron-oxo-porphine model, and the results revealed limitations of the PNPO radical model. Thus, predictive models developed using SE predictors provide rapid and generally internally consistent results, but they should be interpreted and used cautiously.