Optimizing classification of drug-drug interaction potential for CYP450 isoenzyme inhibition assays in early drug discovery
Optimizing classification of drug-drug interaction potential for CYP450 isoenzyme inhibition assays in early drug discovery
复制标题
DOI：
10.1177/1087057106295897
复制
发表时间：
2007-02-01
影响因子：
--
通讯作者：
Huisinga, Wilhelm
中科院分区：
文献类型：
--
作者：
Krippendorff, Ben-Fillippo;Lienau, Philip;Huisinga, Wilhelm
在药物发现中，细胞色素P450对新化学实体的抑制潜力通常用IC50值来量化。在早期药物发现中，将风险分类为低、中、高潜力抑制剂通常足以对化合物进行排序和优先排序。虽然通常使用6个或更多的抑制剂浓度来确定IC50值，但问题是是否有可能基于较少的抑制剂浓度来预测具有相当可靠性的风险等级。在本文中，作者提出了一种新的综合两点方法，根据风险分类选择抑制剂的浓度。他们分析了它的预测能力和可行性，不仅将化合物划分为不同的风险类别，而且还将那些被归类为中等风险类别的化合物进行了排序。因此，所提出的综合两点方法非常适合于自动化。总之，它保持了预测的质量，同时大大减少了时间和成本。建议的方法适用于其他IC50分析和风险分类。
In drug discovery, the potential of cytochrome P450 inhibition of new chemical entities is frequently quantified in terms of IC50 values. In early drug discovery, a risk classification into low, medium, or high potential inhibitors is often sufficient for ranking and prioritizing of compounds. Although often 6 or more inhibitor concentrations are used to determine the IC50 value, the question arises whether it is possible to predict the risk class based on fewer inhibitor concentrations with comparable reliability. In this article, the authors propose a new integrated 2-point method with inhibitor concentrations chosen in accordance with the risk classification. They analyze its predictive power and the feasibility of not only classifying the compounds into different risk classes but also ranking those compounds that have been binned into the middle risk class. The proposed integrated 2-point method is thus highly suitable for automation. Altogether, it maintains the quality of the prediction while considerably reducing time and cost. The proposed method is applicable to other IC50 assays and risk classifications.