In Silico Analysis of Candidate Drugs Against BSEP and MRP2 for their Roles in the Development of DILI



Hepatocytes are polarized cells with specialized transport systems in the canalicular and sinusoidal membrane to maintain hepatic bile acid homeostasis and detoxify endogenous and xenobiotic toxins. The bile salt export pump (BSEP) and Multidrug resistance-associated protein 2 (MRP2) are the two proteins that mediate an ATP-dependent export of conjugated xenobiotic drugs and bilirubin across the canalicular membrane into bile. Functional impairment of BSEP and MRP2 has been hypothesized to play a role in the development of liver injury as a side effect of drug therapy due to their central role in the hepatic excretion of bile acids and toxins. While several experimental studies have confirmed potential BSEP drug inhibitors, the lack of an experimentally validated structure of MRP2 in the Protein Data Bank restricts the scope of extensive ligand binding studies with the protein. Consequently, in silico approaches combined with homology modelling revealed the identity of potential drug inhibitors for the two transporters. Interestingly, studies have supported the hypothesis that the risk of Drug-induced Liver Injury (DILI) may be increased if a compound inhibits not one but both the transporters BSEP and MRP2. In our work, we have attempted to find a correlation between the experimentally determined IC50 values of candidate inhibitors of the two transporters, and their respective in silico binding affinities. Our molecular docking studies revealed that Cyclosporine A, a known inhibitor of the BSEP as well as MRP2 has binding energies of -7.8 kcal/mol and -7.1 kcal/mol respectively for the two proteins. Also, Zafirlukast, another inhibitor of the same transporters has binding energies of -9.2 kcal/mol and -10.3 kcal/mol for BSEP and MRP2 respectively. Both Cyclosporine A and Zafirlukast were predicted to possess developmental toxicity and hepatoxicity. As binding energies are related to magnitude of inhibition, in vitro mutational studies are required to validate the in-silico findings.

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DEY ET AL 2022


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