Novel approach to predicting P450-mediated drug metabolism: Development ofa combined protein and pharmacophore model for CYP2D6

A combined protein and pharmacophore model for cytochrome P450 2D6 (CYP2D6) has been derived using various computational chemistry techniques. A combi nation of pharmacophore modeling (using 40 substrates), protein modeling, a nd molecular orbital calculations was necessary to derive a model which inc orporated steric, electronic, and chemical stability properties. The initia l pharmacophore and protein models used to construct the combined model wer e derived independently and showed a high level of complementarity. The com bined model is in agreement with experimental results concerning the substr ates used to derive the model, with site-directed mutagenesis data availabl e for the CYP2D6 protein, and takes into account the site-directed mutagene sis results for a variety of other 2-family P450s.