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Research ArticleArticle

Three-Dimensional-Quantitative Structure Activity Relationship Analysis of Cytochrome P-450 3A4 Substrates

Sean Ekins, Gianpaolo Bravi, James H. Wikel and Steven A. Wrighton
Journal of Pharmacology and Experimental Therapeutics October 1999, 291 (1) 424-433;
Sean Ekins
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Gianpaolo Bravi
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James H. Wikel
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Steven A. Wrighton
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Abstract

To gain a better understanding of the active site of cytochrome P-450 (CYP) 3A4, a three-dimensional-quantitative structure activity relationship model was constructed using the structures andKm (apparent) values of 38 substrates of human liver microsomal CYP3A4. This pharmacophore was built using the program Catalyst and consisted of four features: two hydrogen bond acceptors, one hydrogen bond donor, and one hydrophobic region. The pharmacophore demonstrated a fit value (r) of observed and expected Km (apparent) value of 0.67. The validity of the CYP3A4 substrate model was tested by twice permuting (randomizing) the activity values and substrate structures. The results of this validation procedure indicated that the original model was a significant representation of the features required of CYP3A4 substrates. The second validation method used the Catalyst model to predict the Km (apparent) values of a test set of structurally diverse substrates for CYP3A4 not included in the 38 molecules used to build the model. Two fitting algorithms included in this software were examined: fast fit and best fit. The fast fitting method resulted in predictions for all 12 substrates that were within 1 log unit for the residual [i.e., the difference between predicted and observed Km (apparent)]. In contrast, the best fit algorithm poorly predicted theKm (apparent) values (i.e., residual >1 log unit) of 4 of 12 substrates. These poor fits with the best fit function suggest that the fast fit method within Catalyst is more representative of the observed Km (apparent) values for CYP3A4 substrates and enables good in silico prediction of this activity. A Catalyst common features pharmacophore was also constructed from three molecules known to activate their own metabolism included in the 38 molecules of the initial CYP3A4 model. This demonstrated that activators of CYP3A4 possess multiple hydrophobic regions that might correspond with a region in the active site away from the metabolic site.

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 46285-0001.

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

  • Abbreviations:
    CYP
    cytochrome P-450
    3D
    three-dimensional
    QSAR
    quantitative structure activity relationship
    • Received September 15, 1999.
    • Accepted May 21, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 1
1 Oct 1999
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Research ArticleArticle

Three-Dimensional-Quantitative Structure Activity Relationship Analysis of Cytochrome P-450 3A4 Substrates

Sean Ekins, Gianpaolo Bravi, James H. Wikel and Steven A. Wrighton
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 424-433;

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Research ArticleArticle

Three-Dimensional-Quantitative Structure Activity Relationship Analysis of Cytochrome P-450 3A4 Substrates

Sean Ekins, Gianpaolo Bravi, James H. Wikel and Steven A. Wrighton
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 424-433;
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