Comprehensive characterization of cytochrome P450 isozyme selectivity across chemical libraries.
Comprehensive characterization of cytochrome P450 isozyme selectivity across chemical libraries.
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DOI：
10.1038/nbt.1581
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发表时间：
2009-11
影响因子：
46.9
通讯作者：
Auld, Douglas S.
中科院分区：
文献类型：
--
作者：
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.
细胞色素 P450 (CYP) 基因家族强烈影响药物开发。我们通过体外生物发光测定确定了 17,143 种化合物针对重组 CYP 1A2、2C9、2C19、2D6 和 3A4 酶的效力值。化合物集合包括来自典型库的物质和 FDA 批准的药物。观察到跨文库同工酶抑制 (30-78%)，且各藏品之间存在显着差异。虽然只有 7% 的典型筛选库对所有五种同工酶都没有活性，但 FDA 批准的药物中有 33% 没有活性，反映了后者优化的药理特性。出乎意料的是，与未优化的集合相比，药物对 CYP 2C9 和 2C19 同工酶的活性较低。然后，我们确定了区分五种同工酶的子结构以及倾向于活性或非活性类别的子结构。我们在这里描述了一个药理学纲要，以进一步了解 CYP 同工酶。
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.
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影响因子：
2.9
作者：
Chauret, N;Tremblay, N;Nicoll-Griffith, DA
通讯作者：
Nicoll-Griffith, DA
影响因子：
3.9
作者：
Foti, Robert S.;Wahlstrom, Jan L.
通讯作者：
Wahlstrom, Jan L.
影响因子：
4.1
作者：
Huang, Ruili;Southall, Noel;Austin, Christopher P.
通讯作者：
Austin, Christopher P.
影响因子：
7.3
作者：
de Graaf, C;Pospisil, P;Vermeulen, NPE
通讯作者：
Vermeulen, NPE
影响因子：
1.8
作者：
Davis, R. Eric;Zhang, Ya-Qin;Auld, Douglas S.
通讯作者：
Auld, Douglas S.