Flagging Drugs That Inhibit the Bile Salt Export Pump

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• 作者：Floriane Montanari ; Marta Pinto ; Narakorn Khunweeraphong ; Katrin Wlcek ; M. Imran Sohail ; Tobias Noeske ; Scott Boyer ; Peter Chiba ; Bruno Stieger ; Karl Kuchler ; Gerhard F. Ecker
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：January 4, 2016
• 年：2016
• 卷：13
• 期：1
• 页码：163-171
• 全文大小：339K
• ISSN：1543-8392

文摘

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.