Novel approach to predicting P450-mediated drug metabolism: development of a combined protein and pharmacophore model for CYP2D6

J Med Chem. 1999 May 6;42(9):1515-24. doi: 10.1021/jm981118h.


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.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Cytochrome P-450 CYP2D6 / chemistry*
  • Cytochrome P-450 CYP2D6 / metabolism
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Pharmaceutical Preparations / metabolism*
  • Protein Conformation
  • Quantum Theory
  • Structure-Activity Relationship


  • Ligands
  • Pharmaceutical Preparations
  • Cytochrome P-450 CYP2D6