Structure-based discovery of potential inhibitors targeting sodium-bile acid co-transporter of carcinogenic liver fluke Clonorchis sinensis

Abstract

Background: Clonorchis sinensis requires bile acid transporters as this fluke inhabits bile juice-filled biliary ducts, which provide an extreme environment. C. sinensis sodium-bile acid co-transporter (CsSBAT) is indispensable for survival in the final host, as it circulates taurocholate and prevents bile toxicity in the fluke; hence, it is recognized as a useful drug target.Results: In the present study, using structure-based drug discovery approach, we presented inhibitor candidates targeting a bile acid-binding pocket of CsSBAT. CsSBAT models were built using comparative tertiary structure modeling based on a bile acid transporter template (PDB ID: 3zuy and 4n7x), and were applied into AutoDock Vina for competitive docking simulation. First, potential compounds were identified from PubChem (holding more than 100,000 compounds) by applying three criteria: i) interacting more favorably with CsSBAT than with a human homolog, ii) intimate interaction to the inward- and outward-facing conformational states, iii) binding with CsSBAT more preferably than natural bile acids. Second, two compounds were identified following Lipinski’s rule of five. Third, another two compounds of molecular weight higher than 500 Da (Mr > 500 Da) were presumed to efficiently block the transporter via a feasible rational screening strategy. These four inhibitor candidates exhibited least toxicity that may enhance drug-likeness properties.Conclusion: It is proposed that four compounds act as potential inhibitors toward CsSBAT, and further studies are warranted for drug development process against clonorchiasis.