A novel approach to predicting P450 mediated drug metabolism. CYP2D6 catalyzed N-dealkylation reactions and qualitative metabolite predictions using a combined protein and pharmacophore model for CYP2D6

A combined protein and pharmacophore model for cytochrome P450 2D6 (CYP2D6) has been extended with a second pharmacophore in order to explain CYP2D6 c atalyzed N-dealkylation reactions. A group of 14 experimentally verified N- dealkylation reactions form the basis of this second pharmacophore. The com bined model can now accommodate both the usual hydroxylation and O-demethyl ation reactions catalyzed by CYP2D6, as well as the less common N-dealkylat ion reactions. The combined model now contains 72 metabolic pathways cataly zed by CYP2D6 in 51 substrates. The model was then used to predict the invo lvement of CYP2D6 in the metabolism of a "test set" of seven compounds. Mol ecular orbital calculations were used to suggest energetically favorable si tes of metabolism, which were then examined using modeling techniques. The combined model correctly predicted 6 of the 8 observed metabolites. For the well-established CYP2D6 metabolic routes, the predictive value of the curr ent-combined protein and pharmacophore model is good. Except for the highly unusual metabolism of procainamide and ritonavir, the known metabolites no t included in the development;of the model were all predicted by the curren t model. Two possible metabolites have been predicted by the current, model , which have not been detected experimentally. In these cases, the model ma y be able to guide experiments. P450 models, like the one presented here, h ave wide applications in the drug design process which will contribute to t he prediction and elimination of polymorphic metabolism and drug-drug inter actions.