title: Optimizing classification of drug-drug interaction potential for CYP450 isoenzyme inhibition assays in early drug discovery.
abstract: 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.
authors.affiliation: Freie Universität Berlin, Department of Mathematics and Computer Science, Berlin, Germany.
authors.forename: Ben-Fillippo
authors.initials: BF
authors.lastname: Krippendorff
authors.forename: Philip
authors.initials: P
authors.lastname: Lienau
authors.forename: Andreas
authors.initials: A
authors.lastname: Reichel
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Huisinga
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors; D015195:Drug Design; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000145:classification* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes