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Comprehensive Characterization of Cytochrome P450 Isozyme Selectivity across Chemical Libraries
The cytochrome P450 (CYP) gene family strongly influences drug development. We determined potency values for 17,143 compounds against recombinant CYP 1A2, 2C9, 2C19, 2D6, and 3A4 enzymes through an in vitro bioluminescent assay. The compound collections included substances from typical libraries and...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783980/ https://www.ncbi.nlm.nih.gov/pubmed/19855396 http://dx.doi.org/10.1038/nbt.1581 |
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author | Veith, Henrike Southall, Noel Huang, Ruili James, Tim Fayne, Darren Artemenko, Natalia Shen, Min Inglese, James Austin, Christopher P. Lloyd, David G. Auld, Douglas S. |
author_facet | Veith, Henrike Southall, Noel Huang, Ruili James, Tim Fayne, Darren Artemenko, Natalia Shen, Min Inglese, James Austin, Christopher P. Lloyd, David G. Auld, Douglas S. |
author_sort | Veith, Henrike |
collection | PubMed |
description | The cytochrome P450 (CYP) gene family strongly influences drug development. We determined potency values for 17,143 compounds against recombinant CYP 1A2, 2C9, 2C19, 2D6, and 3A4 enzymes through an in vitro bioluminescent assay. The compound collections included substances from typical libraries and FDA-approved drugs. Cross-library isozyme inhibition (30–78%) was observed with important differences between collections. While only 7% of the typical screening library was inactive against all five isozymes, 33% of FDA-approved drugs were inactive, reflecting the optimized pharmacological properties of the latter. Unexpectedly, drugs exhibited less activity towards the CYP 2C9 and 2C19 isozymes compared to un-optimized collections. We then identified substructures that differentiated between the five isozymes as well as substructures trending towards active or inactive categories. We describe here a pharmacological compendium to further the understanding of CYP isozymes. |
format | Text |
id | pubmed-2783980 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
record_format | MEDLINE/PubMed |
spelling | pubmed-27839802010-05-01 Comprehensive Characterization of Cytochrome P450 Isozyme Selectivity across Chemical Libraries Veith, Henrike Southall, Noel Huang, Ruili James, Tim Fayne, Darren Artemenko, Natalia Shen, Min Inglese, James Austin, Christopher P. Lloyd, David G. Auld, Douglas S. Nat Biotechnol Article The cytochrome P450 (CYP) gene family strongly influences drug development. We determined potency values for 17,143 compounds against recombinant CYP 1A2, 2C9, 2C19, 2D6, and 3A4 enzymes through an in vitro bioluminescent assay. The compound collections included substances from typical libraries and FDA-approved drugs. Cross-library isozyme inhibition (30–78%) was observed with important differences between collections. While only 7% of the typical screening library was inactive against all five isozymes, 33% of FDA-approved drugs were inactive, reflecting the optimized pharmacological properties of the latter. Unexpectedly, drugs exhibited less activity towards the CYP 2C9 and 2C19 isozymes compared to un-optimized collections. We then identified substructures that differentiated between the five isozymes as well as substructures trending towards active or inactive categories. We describe here a pharmacological compendium to further the understanding of CYP isozymes. 2009-10-25 2009-11 /pmc/articles/PMC2783980/ /pubmed/19855396 http://dx.doi.org/10.1038/nbt.1581 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Veith, Henrike Southall, Noel Huang, Ruili James, Tim Fayne, Darren Artemenko, Natalia Shen, Min Inglese, James Austin, Christopher P. Lloyd, David G. Auld, Douglas S. Comprehensive Characterization of Cytochrome P450 Isozyme Selectivity across Chemical Libraries |
title | Comprehensive Characterization of Cytochrome P450 Isozyme Selectivity across Chemical Libraries |
title_full | Comprehensive Characterization of Cytochrome P450 Isozyme Selectivity across Chemical Libraries |
title_fullStr | Comprehensive Characterization of Cytochrome P450 Isozyme Selectivity across Chemical Libraries |
title_full_unstemmed | Comprehensive Characterization of Cytochrome P450 Isozyme Selectivity across Chemical Libraries |
title_short | Comprehensive Characterization of Cytochrome P450 Isozyme Selectivity across Chemical Libraries |
title_sort | comprehensive characterization of cytochrome p450 isozyme selectivity across chemical libraries |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783980/ https://www.ncbi.nlm.nih.gov/pubmed/19855396 http://dx.doi.org/10.1038/nbt.1581 |
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