Krippendorff, Ben-Fillippo and Lienau, Philip and Reichel, Andreas and Huisinga, Wilhelm
Optimizing Classification of Drug-Drug Interaction Potential for CYP450 Iso-Enzymes Inhibition Assays in Early Drug Discovery.
Journal of Biomolecular Screening, 12 (1).
In drug discovery, the potential of cytochrome P450 inhibition of new chemical entities (NCEs) 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. While often six 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 the present article we propose a new integrated twopoint method with inhibitor concentrations chosen in accordance with the risk-classification. We analyse its predictive power and the feasibility to not only classify the compounds into different risk classes but also rank those compounds that have been binned into the middle risk class. The proposed integrated two 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.
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