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Mol Pharm. 2016 Jan 4;13(1):163-71. doi: 10.1021/acs.molpharmaceut.5b00594. Epub 2015 Dec 21.

Flagging Drugs That Inhibit the Bile Salt Export Pump.

Author information

1
Department of Pharmaceutical Chemistry, University of Vienna , Althanstrasse 14, 1090 Vienna, Austria.
2
Max F. Perutz Laboratories, Medical University of Vienna , Vienna Biocenter, 1030 Vienna, Austria.
3
Institute of Medical Chemistry, Medical University of Vienna , Waehringerstrasse 10, 1090 Vienna, Austria.
4
Drug Safety and Metabolism, AstraZeneca R&D Mölndal , Pepparedsleden 1, Mölndal 43183, Sweden.
5
Department of Clinical Pharmacology and Toxicology, University Hospital , 8091 Zurich, Switzerland.

Abstract

The bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepatocytes. Its physiological role is to expel bile salts into the canaliculi from where they drain into the bile duct. Inhibition of this transporter may lead to intrahepatic cholestasis. Predictive computational models of BSEP inhibition may allow for fast identification of potentially harmful compounds in large databases. This article presents a predictive in silico model based on physicochemical descriptors that is able to flag compounds as potential BSEP inhibitors. This model was built using a training set of 670 compounds with available BSEP inhibition potencies. It successfully predicted BSEP inhibition for two independent test sets and was in a further step used for a virtual screening experiment. After in vitro testing of selected candidates, a marketed drug, bromocriptin, was identified for the first time as BSEP inhibitor. This demonstrates the usefulness of the model to identify new BSEP inhibitors and therefore potential cholestasis perpetrators.

KEYWORDS:

BSEP; bromocriptin; classification model; drug-induced cholestasis; inhibition

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