Flagging Drugs That Inhibit the Bile Salt Export Pump

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.