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

Suparna Dey

Abstract


Hepatocytes are polarized cells that have specialized transport systems in the canalicular/apical and sinusoidal/basolateral membrane to maintain hepatic bile acid homeostasis and detoxify endogenous and xenobiotic toxins. Under physiologic conditions, the bile salt export pump (BSEP) and Multidrug resistance-associated protein 2 (MRP2) , are the two proteins that mediate an ATP-dependent export of xenobiotic drug conjugates and conjugated bilirubin across the canalicular membrane into bile, where they can form micelles with other bile components such as phospholipids or cholesterol. Owing to their central role in the hepatic excretion of bile acids and toxins, functional impairment of BSEP and MRP2 has been hypothesized to play a role in the development of liver injury often as a side effect of drug therapy. While several experimental studies have confirmed the potential drug inhibitors of BSEP, the lack of an experimentally validated structure of MRP2 in the Protein Data Bank limits the scope of extensive ligand binding studies with the protein. Consequently, in silico approaches in combination with homology modelling have unveiled the identity of several candidate drug inhibitors for the two liver transporters for a comparative analysis . Studies in the same line have also supported the hypothesis that the risk of Drug Induced Liver Injury (DILI) may be even greater if a compound inhibits not just one but both the hepatic bile acid transporters BSEP and MRP2. Therefore, if the compound under study is a BSEP inhibitor, the inhibitory potency on MRP2 should also be evaluated to improve the correlation with liver injury compared with inhibition of BSEP Or MRP2 inhibition alone. In this work, we have attempted to find a correlation between the experimentally determined IC50 values of four drugs namely pioglitazone, cyclosporine A, papaverine and acyclovir, and their respective in silico binding affinities to BSEP and MRP2. Molecular docking studies showed that the drugs with lower IC50 values (cyclosporine A and pioglitazone) had more negative binding energies when compared to the ones with higher IC50 values (papaverine and acyclovir). Since the binding energies tie in with the magnitude of inhibition, further experimental mutation studies are required to confirm the in silico findings.

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SUPARNA ET AL

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