Conformer- and alignment-independent model for predicting structurally diverse competitive CYP2C9 inhibitors

J Med Chem. 2004 Feb 12;47(4):907-14. doi: 10.1021/jm030972s.


A conformer- and alignment-independent three-dimensional structure-activity relationship (3D-QSAR) model has been derived that is based on flexible molecular interaction fields calculated in GRID and the subsequent description of these fields by use of alignment-independent descriptors derived in ALMOND. The training set consisted of 22 diverse and flexible competitive inhibitors of the drug-metabolizing enzyme CYP2C9 and generated a model with r(2) of 0.81 and q(2) of 0.62. The predicitive capacity of the model was externally evaluated with a test set of 12 competitive inhibitors and 11 out of 12 were predicted within 0.5 log unit. The most relevant points of interaction in the model correlated well to the amino acids involved in CYP2C9-substrate/inhibitor binding in the active site of a CYP2C9 homology model, further validating the mechanistic sense of our model. This approach offers the possibility to derive predicitve 3D-QSAR models without the need for an alignment rule for chemically diverse ligands and in the absence of target protein crystal structure information.

MeSH terms

  • Amino Acids / chemistry
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
  • Aryl Hydrocarbon Hydroxylases / chemistry*
  • Binding Sites
  • Cytochrome P-450 CYP2C9
  • Enzyme Inhibitors / chemistry*
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Quantitative Structure-Activity Relationship


  • Amino Acids
  • Enzyme Inhibitors
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases