TY - JOUR T1 - Computational Models for Cytochrome P450: A Predictive Electronic Model for Aromatic Oxidation and Hydrogen Atom Abstraction JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 7 LP - 12 DO - 10.1124/dmd.30.1.7 VL - 30 IS - 1 AU - Jeffrey P. Jones AU - Michael Mysinger AU - Kenneth Ray Korzekwa Y1 - 2002/01/01 UR - http://dmd.aspetjournals.org/content/30/1/7.abstract N2 - Experimental observations suggest that electronic characteristics play a role in the rates of substrate oxidation for cytochrome P450 enzymes. For example, the tendency for oxidation of a certain functional group generally follows the relative stability of the radicals that are formed (e.g., N-dealkylation >O-dealkylation > 2° carbon oxidation > 1° carbon oxidation). In addition, results show that useful correlations between the rates of product formation can be developed using electronic models. In this article, we attempt to determine whether a combined computational model for aromatic and aliphatic hydroxylation can be developed. Toward this goal, we used a combination of experimental data and semiempirical molecular orbital calculations to predicted activation energies for aromatic and aliphatic hydroxylation. The resulting model extends the predictive capacity of our previous aliphatic hydroxylation model to include the second most important group of oxidations, aromatic hydroxylation. The combined model can account for about 83% of the variance in the data for the 20 compounds in the training set and has an error of about 0.7 kcal/mol. The American Society for Pharmacology and Experimental Therapeutics ER -