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Quantitative Binding Models for CYP2C9 Based on Benzbromarone Analogues

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School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, and Department of Chemistry, Washington State University, P.O. Box 644630, Pullman, Washington 99164-4630
Cite this: Biochemistry 2004, 43, 22, 6948–6958
Publication Date (Web):May 13, 2004
https://doi.org/10.1021/bi049651o
Copyright © 2004 American Chemical Society

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    Abstract

    The cytochrome P450 (CYP) isoforms involved in xenobiotic metabolism are enzymes whose substrate selectivity remains difficult to predict due to wide specificity and dynamic protein−substrate interactions. To uncover the determinants of specificity for cytochrome CYP2C9, a novel library of benzbromarone (bzbr) inhibitors was used to reevaluate its pharmacophore. CoMSIA was used with the bzbr ligands to generate both quantitative binding models and three-dimensional contour plots that pinpoint predicted interactions that are important for binding to 2C9. Since this class of compounds is more potent than any other toward 2C9, the small molecule properties deemed most ideal by the software were used to address protein−ligand interactions using new mutagenesis and structural data. Nine new bzbr analogues provide evidence that specific electrostatic and hydrophobic interactions contribute the most to 2C9's specificity. Three of the new analogues are better isosteres of bzbr that contain bulky groups adjacent to the phenol and have increased pKa values. These ligands test the hypothesis that anionic substrates bind with higher affinity to 2C9. Since they have higher affinity than the previous nonacidic analogues, the importance of bulky groups on the phenol ring appears to have been underestimated. CoMSIA models predict that these bulky groups are favorable for their hydrophobicity, while a negative charge is favored at the ketone oxygen rather than the phenol oxygen. The overlap of this ketone with electronegative groups of other 2C9 substrates suggests they act as key positive charge acceptors.

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     This work was supported by National Institutes of Health Grants GM032165 and ES009122.

     School of Molecular Biosciences.

    §

     Department of Chemistry.

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    In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

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