title: Novel approach to predicting P450-mediated drug metabolism: development of a combined protein and pharmacophore model for CYP2D6.
abstract: 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.
authors.affiliation: Departments of Computational Chemistry and Drug Metabolism, Pfizer Central Research, Sandwich, Kent CT13 9NJ, United Kingdom.
authors.forename: M J
authors.initials: MJ
authors.lastname: de Groot
authors.forename: M J
authors.initials: MJ
authors.lastname: Ackland
authors.forename: V A
authors.initials: VA
authors.lastname: Horne
authors.forename: A A
authors.initials: AA
authors.lastname: Alex
authors.forename: B C
authors.initials: BC
authors.lastname: Jones
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011487:Protein Conformation; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D019389:Cytochrome P-450 CYP2D6