Flagging Drugs That Inhibit the Bile Salt Export Pump

Area of Science:

• Hepatology and Drug Metabolism
• Computational Toxicology

Background:

• The bile salt export pump (BSEP) is vital for excreting bile salts from hepatocytes.
• BSEP inhibition can result in intrahepatic cholestasis, a serious liver condition.

Purpose of the Study:

• To develop and validate an in silico model for predicting BSEP inhibitors.
• To identify novel BSEP inhibitors using computational screening.

Main Methods:

• A predictive model was built using physicochemical descriptors and a training set of 670 compounds.
• The model was validated on independent test sets.
• Virtual screening was performed, followed by in vitro testing of selected compounds.

Main Results:

• The in silico model accurately predicted BSEP inhibition in test sets.
• Virtual screening identified potential BSEP inhibitors.
• Bromocriptine was identified as a novel BSEP inhibitor through in vitro testing.

Conclusions:

• The developed in silico model is effective for identifying potential BSEP inhibitors.
• This approach aids in the early detection of compounds that may cause cholestasis.
• The study identified bromocriptine as a previously unrecognized BSEP inhibitor.