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A combined protein and pharmacophore model for cytochrome P450 2D6 (CYP2D6) has been extended with a second pharmacophore in order to explain CYP2D6 catalyzed N-dealkylation reactions. A group of 14 experimentally verified N-dealkylation reactions form the basis of this second pharmacophore. The combined model can now accommodate both the usual hydroxylation and O-demethylation reactions catalyzed by CYP2D6, as well as the less common N-dealkylation reactions. The combined model now contains 72 metabolic pathways catalyzed by CYP2D6 in 51 substrates. The model was then used to predict the involvement of CYP2D6 in the metabolism of a "test set" of seven compounds. Molecular orbital calculations were used to suggest energetically favorable sites 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 current combined protein and pharmacophore model is good. Except for the highly unusual metabolism of procainamide and ritonavir, the known metabolites not included in the development of the model were all predicted by the current model. Two possible metabolites have been predicted by the current model, which have not been detected experimentally. In these cases, the model may be able to guide experiments. P450 models, like the one presented here, have wide applications in the drug design process which will contribute to the prediction and elimination of polymorphic metabolism and drug-drug interactions.

A combined protein and pharmacophore model for cytochrome P450 2D6 (CYP2D6) has been derived using various computational chemistry techniques. A combination of pharmacophore modeling (using 40 substrates), protein modeling, and molecular orbital calculations was necessary to derive a model which incorporated steric, electronic, and chemical stability properties. The initial pharmacophore and protein models used to construct the combined model were derived independently and showed a high level of complementarity. The combined model is in agreement with experimental results concerning the substrates used to derive the model, with site-directed mutagenesis data available for the CYP2D6 protein, and takes into account the site-directed mutagenesis results for a variety of other 2-family P450s.