Modeling the Effect of BSEP Inhibitors in Lipid Bilayers by Means of All-Atom Molecular Dynamics Simulation

Abstract

The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates the active transport of unconjugated and conjugated bile salts from liver cells into bile. Genetically inherited defects in BSEP expression or activity causes cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo, suggesting that this could be one of the mechanisms that initiates human DILI. The relationship between BSEP inhibition and molecular physicochemical properties has been previously investigated, identifying calculated lipophilicity and molecular weight to be significantly correlated with the BSEP inhibition. Predictive BSEP classification models, constructed through multiple quantitative structure–activity relationship modeling approaches, exhibit significant anomalies with differences in experimental IC50 values of three orders of magnitude...