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Mol Pharm. 2015 Dec 7;12(12):4395-404. doi: 10.1021/acs.molpharmaceut.5b00583. Epub 2015 Nov 2.

Identification of Novel Inhibitors of Organic Anion Transporting Polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) Using a Consensus Vote of Six Classification Models.

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Department of Pharmaceutical Chemistry, University of Vienna , Althanstrasse 14, 1090 Vienna, Austria.


Organic anion transporting polypeptides 1B1 and 1B3 are transporters selectively expressed on the basolateral membrane of the hepatocyte. Several studies reveal that they are involved in drug-drug interactions, cancer, and hyperbilirubinemia. In this study, we developed a set of classification models for OATP1B1 and 1B3 inhibition based on more than 1700 carefully curated compounds from literature, which were validated via cross-validation and by use of an external test set. After combining several sets of descriptors and classifiers, the 6 best models were selected according to their statistical performance and were used for virtual screening of DrugBank. Consensus scoring of the screened compounds resulted in the selection and purchase of nine compounds as potential dual inhibitors and of one compound as potential selective OATP1B3 inhibitor. Biological testing of the compounds confirmed the validity of the models, yielding an accuracy of 90% for OATP1B1 and 80% for OATP1B3, respectively. Moreover, at least half of the new identified inhibitors are associated with hyperbilirubinemia or hepatotoxicity, implying a relationship between OATP inhibition and these severe side effects.


DrugBank; OATP1B1; OATP1B3; Random Forest; Support Vector Machines; classification; hepatocyte; inhibitors; liver; organic anion transporting polypeptide B1; organic anion transporting polypeptide B3; transporters; virtual screening

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