Cytochrome P450 2C9 type II binding studies on quinoline-4-carboxamide analogues

J Med Chem. 2008 Dec 25;51(24):8000-11. doi: 10.1021/jm8011257.


CYP2C9 is a significant P450 protein responsible for drug metabolism. With the increased use of heterocyclic compounds in drug design, a rapid and efficient predrug screening of these potential type II binding compounds is essential to avoid adverse drug reactions. To understand binding modes, we use quinoline-4-carboxamide analogues to study the factors that determine the structure-activity relationships. The results of this study suggest that the more accessible pyridine with the nitrogen para to the linkage can coordinate directly with the ferric heme iron, but this is not seen for the meta or ortho isomers. The pi-cation interaction of the naphthalene moiety and Arg 108 residue may also assist in stabilizing substrate binding within the active-site cavity. The type II substrate binding affinity is determined by the combination of steric, electrostatic, and hydrophobicity factors; meanwhile, it is enhanced by the strength of lone pair electrons coordination with the heme iron.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Arginine / chemistry
  • Aryl Hydrocarbon Hydroxylases / chemistry*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Catalytic Domain
  • Chemistry, Pharmaceutical / methods*
  • Cytochrome P-450 CYP2C9
  • Drug Design
  • Heme / chemistry
  • Humans
  • Imidazoles / chemistry*
  • Iron / chemistry
  • Models, Molecular
  • Molecular Conformation
  • Protein Binding
  • Quinolines / chemistry*
  • Structure-Activity Relationship
  • Substrate Specificity


  • Imidazoles
  • Quinolines
  • Heme
  • Arginine
  • Iron
  • quinoline
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases