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Molecular Pharmacology

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Research ArticleArticle

Competitive CYP2C9 Inhibitors: Enzyme Inhibition Studies, Protein Homology Modeling, and Three-Dimensional Quantitative Structure-Activity Relationship Analysis

Lovisa Afzelius, Ismael Zamora, Marianne Ridderström, Tommy B. Andersson, Anders Karlén and Collen M. Masimirembwa
Molecular Pharmacology April 2001, 59 (4) 909-919; DOI: https://doi.org/10.1124/mol.59.4.909
Lovisa Afzelius
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Ismael Zamora
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Marianne Ridderström
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Tommy B. Andersson
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Anders Karlén
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Collen M. Masimirembwa
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Abstract

This study describes the generation of a three-dimensional quantitative structure activity relationship (3D-QSAR) model for 29 structurally diverse, competitive CYP2C9 inhibitors defined experimentally from an initial data set of 73 compounds. In parallel, a homology model for CYP2C9 using the rabbit CYP2C5 coordinates was built. For molecules with a known interaction mode with CYP2C9, this homology model, in combination with the docking program GOLD, was used to select conformers to use in the 3D-QSAR analysis. The remaining molecules were docked, and the GRID interaction energies for all conformers proposed by GOLD were calculated. This was followed by a principal component analysis (PCA) of the GRID energies for all conformers of all compounds. Based on the similarity in the PCA plot to the inhibitors with a known interaction mode, the conformer to be used in the 3D-QSAR analysis was selected. The compounds were randomly divided into two groups, the training data set (n = 21) to build the model and the external validation set (n = 8). The PLS (partial least-squares) analysis of the interaction energies against the K i values generated a model with r2 = 0.947 and a cross-validation of q2 = 0.730. The model was able to predict the entire external data set within 0.5 log units of the experimentalK i values. The amino acids in the active site showed complementary features to the grid interaction energies in the 3D-QSAR model and were also in agreement with mutagenesis studies.

Footnotes

    • Received October 3, 2000.
    • Accepted December 20, 2000.
  • Send reprint requests to: Collen M. Masimirembwa, Department of DMPK & Bioanalytical Chemistry, AstraZeneca R & D Mölndal, S-431 83 Mölndal, Sweden. E-mail:collen.masimirembwa{at}astrazeneca.com

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Molecular Pharmacology: 59 (4)
Molecular Pharmacology
Vol. 59, Issue 4
1 Apr 2001
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Research ArticleArticle

Competitive CYP2C9 Inhibitors: Enzyme Inhibition Studies, Protein Homology Modeling, and Three-Dimensional Quantitative Structure-Activity Relationship Analysis

Lovisa Afzelius, Ismael Zamora, Marianne Ridderström, Tommy B. Andersson, Anders Karlén and Collen M. Masimirembwa
Molecular Pharmacology April 1, 2001, 59 (4) 909-919; DOI: https://doi.org/10.1124/mol.59.4.909

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Research ArticleArticle

Competitive CYP2C9 Inhibitors: Enzyme Inhibition Studies, Protein Homology Modeling, and Three-Dimensional Quantitative Structure-Activity Relationship Analysis

Lovisa Afzelius, Ismael Zamora, Marianne Ridderström, Tommy B. Andersson, Anders Karlén and Collen M. Masimirembwa
Molecular Pharmacology April 1, 2001, 59 (4) 909-919; DOI: https://doi.org/10.1124/mol.59.4.909
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