The data set was randomly split with a ratio of 2:1 into a training set of 163 compounds selleckchem Abiraterone (34 strong inhibitors, 21 weak inhibitors, and 108 noninhibitors) for model development and a test set of 86 compounds (19 strong inhibitors, 12 weak inhibitors, and 55 noninhibitors) for validation of the final model. Chemical structures were obtained as 2D SD files from PubChem (Bolton et al., 2008). These structures were further processed to calculate molecular descriptors using the Dragon version 6 (Talete, Italy), ADMETPredictor version 6.0 (SimulationsPlus, Lancaster, CA), and MAREA version 3.02 (in-house) software. The descriptors were related to the inhibition class using orthogonal partial least-squares projection to latent structures discriminant analysis (OPLS-DA), according to a previous protocol (Pedersen et al.

, 2008). Classifying DILI severity of drugs in the data set. The main goal of this investigation was to explore to what extent BSEP inhibition predicts clinically observed DILI. We identified the classification system of adverse drug reactions (ADR) implemented in the FDA drug labels as a suitable data source. The FDA drug labels represent a consensus of regulatory and industry experts who evaluate and balance data combined from controlled clinical trials, published literature case studies, spontaneous ADR reports, and postmarket monitoring. The 3 ADR sections within the drug labels categorize ADRs by increasing severity, ranging from the least severe ��adverse reactions�� (AR), through the intermediate ��warnings and precautions�� (WP), to the most severe ��boxed warnings�� (BW).

According to the definitions in U.S. federal regulations 21 CFR 201.57, the AR section describes the overall adverse reaction profile of a drug and includes those adverse events believed to have a causal relationship with the drug. The WP section is required to describe clinically significant adverse reactions as soon as reasonable evidence of a causal association with the drug is established. The BW section contains certain contraindications or serious warnings, particularly those that may lead to death or serious injury, and is generally based on clinical data (U.S. Federal Regulations, 2012). To assess the DILI potential of registered drugs within the data set, information on hepatic ADRs in FDA-approved drug labels was obtained from DailyMed (http://dailymed.nlm.nih.gov/), and the DILI potential was classified using the method of Chen et al. (2011). Briefly, FDA drug labels were reviewed for hepatic adverse reactions by searching for keywords related to liver injury (Supplementary Table S1). A compound was regarded as a DILI mediator if the keywords were identified Entinostat in the BW, WP, or AR sections within a drug label.