Generation and evaluation of a CYP2C9 heteroactivation pharmacophore.

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Egnell AC, Eriksson C, Albertson N, Houston B, Boyer S

Generation and evaluation of a CYP2C9 heteroactivation pharmacophore.

J Pharmacol Exp Ther. 2003 Dec;307(3):878-87. Epub 2003 Oct 13.

PubMed ID

14557374 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Estrone sulfate	Cytochrome P450 2C9	Protein	Humans	Unknown	Substrate Inhibitor	Details
Niclosamide	Cytochrome P450 2C9	Protein	Humans	Unknown	Substrate	Details