title: Flagging Drugs That Inhibit the Bile Salt Export Pump.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna , Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Floriane
authors.initials: F
authors.lastname: Montanari
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna , Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Marta
authors.initials: M
authors.lastname: Pinto
authors.affiliation: Max F. Perutz Laboratories, Medical University of Vienna , Vienna Biocenter, 1030 Vienna, Austria.
authors.forename: Narakorn
authors.initials: N
authors.lastname: Khunweeraphong
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna , Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Wlcek
authors.affiliation: Institute of Medical Chemistry, Medical University of Vienna , Waehringerstrasse 10, 1090 Vienna, Austria.
authors.forename: M Imran
authors.initials: MI
authors.lastname: Sohail
authors.affiliation: Drug Safety and Metabolism, AstraZeneca R&D Mölndal , Pepparedsleden 1, Mölndal 43183, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Noeske
authors.affiliation: Drug Safety and Metabolism, AstraZeneca R&D Mölndal , Pepparedsleden 1, Mölndal 43183, Sweden.
authors.forename: Scott
authors.initials: S
authors.lastname: Boyer
authors.affiliation: Institute of Medical Chemistry, Medical University of Vienna , Waehringerstrasse 10, 1090 Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Chiba
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital , 8091 Zurich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.affiliation: Max F. Perutz Laboratories, Medical University of Vienna , Vienna Biocenter, 1030 Vienna, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Kuchler
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna , Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology*; D016466:CHO Cells; D002460:Cell Line; D002779:Cholestasis / Q000517:prevention & control; D003198:Computer Simulation; D003412:Cricetulus; D013552:Swine
chemical_list: D018528:ATP-Binding Cassette Transporters; D001971:Bromocriptine
keywords: BSEP; bromocriptin; classification model; drug-induced cholestasis; inhibition