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Research ArticleArticle

Three-Dimensional Quantitative Structure Activity Relationship Analyses of Substrates for CYP2B6

Sean Ekins, Gianpaolo Bravi, Barbara J. Ring, Todd A. Gillespie, Jennifer S. Gillespie, Mark Vandenbranden, Steven A. Wrighton and James H. Wikel
Journal of Pharmacology and Experimental Therapeutics January 1999, 288 (1) 21-29;
Sean Ekins
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Gianpaolo Bravi
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Barbara J. Ring
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Todd A. Gillespie
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Jennifer S. Gillespie
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Mark Vandenbranden
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Steven A. Wrighton
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James H. Wikel
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Abstract

To begin to build an understanding of the interactions of CYP2B6 with substrates, two different 3-dimensional quantitative structure activity relationship (3D-QSAR) models were constructed using 16 substrates of B-lymphoblastoid expressed CYP2B6. A pharmacophore model was built using the program Catalyst, which was compared with a partial least-squares (PLS) model using molecular surface-weighted holistic invariant molecular (MS-WHIM) descriptors. The Catalyst model yielded a 3-dimensional model of the common structural features of CYP2B6 substrates, whereas PLS MS-WHIM generated a model based on statistical analyses of molecular descriptors for size and shape of the substrate. The pharmacophore model obtained with Catalyst consisted of three hydrophobes and one hydrogen bond acceptor region. The cross-validated PLS MS-WHIM model gave a good q2 value of 0.607. Size, positive electrostatic potential, hydrogen bonding acceptor capacity, and hydrophobicity were found to be the most relevant descriptors for the model. These models were then used to predict the Km (apparent) values of a test set of structurally diverse substrates for CYP2B6 not included in the model building, specifically lidocaine, amitriptyline, bupropion, arteether, and verapamil. Overall, both 3D-QSAR methods yielded satisfactory Km (apparent) value predictions for the majority of the molecules in the test set. However, PLS MS-WHIM was unable to reliably predict theKm (apparent) value for verapamil, whereas Catalyst did not predict the Km (apparent)value for lidocaine. In both of these cases the residual of theKm (apparent) value was greater than one log unit. The strengths and limitations of both of these 3D-QSAR approaches are discussed.

Footnotes

  • Send reprint requests to: Steven A. Wrighton, Ph.D., Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Drop Code 0825, Indianapolis, IN 46203.

  • ↵1 Present address: Central Research Division, Pfizer Inc., Groton, CT 06340.

  • ↵2 Present address: Glaxo Wellcome Research and Development, Medicines Research Center, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.

  • Abbreviations:
    CYP
    cytochrome P-450
    3D-QSAR
    3-dimensional quantitative structure activity relationship
    LOO
    leave one out
    MS-WHIM
    molecular surface-weighted holistic invariant molecular
    PLS
    partial least squares
    5RGx100
    five random groups repeated up to 100 times
    3D
    3-dimensional
    MEGX
    monoethylglycinexylidide
    HPLC
    high-performance liquid chromatography, LC/MS, liquid chromatography/mass spectroscopy
    LC/MS/MS
    liquid chromatography/mass spectroscopy/mass spectroscopy
    • Received March 26, 1998.
    • Accepted August 26, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 1
1 Jan 1999
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Research ArticleArticle

Three-Dimensional Quantitative Structure Activity Relationship Analyses of Substrates for CYP2B6

Sean Ekins, Gianpaolo Bravi, Barbara J. Ring, Todd A. Gillespie, Jennifer S. Gillespie, Mark Vandenbranden, Steven A. Wrighton and James H. Wikel
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 21-29;

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Research ArticleArticle

Three-Dimensional Quantitative Structure Activity Relationship Analyses of Substrates for CYP2B6

Sean Ekins, Gianpaolo Bravi, Barbara J. Ring, Todd A. Gillespie, Jennifer S. Gillespie, Mark Vandenbranden, Steven A. Wrighton and James H. Wikel
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 21-29;
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