Cytochrome P450 2C9 Type II Binding Studies on Quinoline-4-Carboxamide Analogues

• Published in: Journal of medicinal chemistry Vol. 51; no. 24; pp. 8000 - 8011
• Main Authors: Peng, Chi-Chi, Cape, Jonathan L, Rushmore, Tom, Crouch, Gregory J, Jones, Jeffrey P
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.12.2008; Amer Chemical Soc
• Subjects: Arginine - chemistry; Aryl Hydrocarbon Hydroxylases - chemistry; Aryl Hydrocarbon Hydroxylases - metabolism; Biological and medical sciences; Catalytic Domain; Chemistry, Medicinal; Chemistry, Pharmaceutical - methods; Cytochrome P-450 CYP2C9; Drug Design; Heme - chemistry; Humans; Imidazoles - chemistry; Iron - chemistry; Life Sciences & Biomedicine; Medical sciences; Miscellaneous; Models, Molecular; Molecular Conformation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Binding; Quinolines - chemistry; Science & Technology; Structure-Activity Relationship; Substrate Specificity; INHIBITORY POTENCY; CYP2C9; P450 INTERACTION; CORRELATED MOLECULAR CALCULATIONS; SPIN-STATE; METABOLIC STABILITY; SPECTRA; AFFINITIES; DRUG-DRUG INTERACTIONS; GAUSSIAN-BASIS SETS; Unspecific monooxygenase; Enzyme; Isozyme; Cytochrome P450; EPR spectrometry; Quinoline derivatives; Naphthalene derivatives; In vitro; Pyridine derivatives; Structure activity relation; Binding mode; Carboxamide; Drug-metabolizing enzyme; Oxidoreductases; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• 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 π−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.