Novel approach to predicting P450-mediated drug metabolism: development of a 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 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.
de Groot
M J
MJ
Departments of Computational Chemistry and Drug Metabolism, Pfizer Central Research, Sandwich, Kent CT13 9NJ, United Kingdom.
Ackland
M J
MJ
Horne
V A
VA
Alex
A A
AA
Jones
B C
BC
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
D008024:Ligands; D004364:Pharmaceutical Preparations; D019389:Cytochrome P-450 CYP2D6