| Title | Generation and evaluation of a CYP2C9 heteroactivation pharmacophore. | | Author(s) | Egnell AC, Eriksson C, Albertson N, Houston B, Boyer S | | Institution | AstraZeneca R and D, EST Chemical Computing, S-43183 Mölndal, Sweden. ann-charlotte.egnell@astrazeneca.com | | Source | J Pharmacol Exp Ther 2003 Dec; 307(3):878-87. | | MeSH | Aryl Hydrocarbon Hydroxylases
Chromatography, High Pressure Liquid
Drug Design
Drug Evaluation, Preclinical
Enzyme Activation
Enzyme Activators
Kinetics
Models, Molecular
Reproducibility of Results
Structure-Activity Relationship
| | Abstract | Positive cooperativity (auto- and heteroactivation) of drug oxidation, a potential cause of drug interactions, is well established in vitro for cytochrome P450 (P450) 3A4 but to a much lesser extent for other drug-metabolizing P450 isoforms. Using a high throughput fluorescent-based CYP2C9 effector assay, we identified >30 heteroactivators from a set of 1504 structurally diverse compounds. Several potent heteroactivators of CYP2C9-mediated 7-methoxy-4-trifluoromethyl-coumarin metabolism are marketed drugs or endogenous compounds (amiodarone, niclosamide, liothyronine, meclofenemate, zafirlukast, estropipate, and dichlorphenamide, yielding 150% control reaction velocity at 0.04, 0.09, 0.5, 1, 1.2, 1.5, and 2.5 microM, respectively). Some heteroactivators are also known CYP2C9 substrates or inhibitors, suggesting potential multiple binding sites and substrate-dependent effects. v(150%), the concentration of effector giving 150% of control reaction velocity, was used as pharmacophore modeling parameter based on enzyme kinetic assumptions. The generated pharmacophore (training set: n = 36, v(150%) 0.04-150 microM) contains one hydrogen bond acceptor, one aromatic ring, and two hydrophobes. v(150%) values for 94% of the training set heteroactivators were predicted within 1 log unit for the residual (r [log observed v(150%)] versus [log predicted v(150%)] = 0.71; r2 0.50). The model also correctly identifies close to 70% of potent inhibitors (IC50 < 1 microM) as high-affinity CYP2C9 binders, suggesting that heteroactivators and inhibitors share some common structural CYP2C9 binding features, supporting the previously suggested hypothesis that CYP2C9 heteroactivators can bind within the active site. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 14557374 |
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