1. Structure-based virtual screening and molecular dynamics of potential inhibitors targeting sodium-bile acid co-transporter of carcinogenic liver fluke Clonorchis sinensis.
- Author
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Yoo, Won Gi, Dai, Fuhong, Pak, Jhang Ho, Hong, Sung-Jong, and Song, Jin-Ho
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CLONORCHIS sinensis , *LIVER flukes , *MOLECULAR dynamics , *BILE acids , *TERTIARY structure , *CANAGLIFLOZIN , *SODIUM-glucose cotransporters - Abstract
Background: Clonorchis sinensis requires bile acid transporters as this fluke inhabits bile juice-filled biliary ducts, which provide an extreme environment. Clonorchis sinensis sodium-bile acid co-transporter (CsSBAT) is indispensable for the fluke's 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. Methodology and principal findings: In the present study, using structure-based virtual screening approach, we presented inhibitor candidates targeting a bile acid-binding pocket of CsSBAT. CsSBAT models were built using 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 preferably to natural bile acids. Second, two compounds were identified following the Lipinski's rule of five. Third, other 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. Of these candidates, compound 9806452 exhibited the least hepatotoxicity that may enhance drug-likeness properties. Conclusions: It is proposed that compound 9806452 act as a potential inhibitor toward CsSBAT and further studies are warranted for drug development process against clonorchiasis. Author summary: Clonorchis sinensis, the Chinese liver fluke, is a parasite infecting human. People are infected via ingesting raw freshwater fishes carrying C. sinensis metacercariae, the encysted form of larvae. Clonorchiasis is a disease caused by C. sinensis, which affects primarily the host hepatobiliary organs. World Health Organization has classified C. sinensis as a biological carcinogen inducing cholangiocarcinoma. Praziquantel has been a therapeutical choice for clonorchiasis. However, the flukes resistant to the drug have emerged due to the extensive use of it. Hence, it is necessary to develop new chemotherapeutic agents to outwit the drug-resistant worms. Sodium-dependent bile acid transporter of C. sinensis (CsSBAT) is essential for the survival of C. sinensis in the bile environment. When CsSBAT is inhibited, bile acids accumulate in the worm's tissues and cells, which are detrimental to the survival of the worm. Structure-based virtual screening is a powerful approach for compound identification and drug development. Here, we prepared CsSBAT structures using tertiary structure modeling and refinement. We identified four putative inhibitory compounds, which competitively targeted the bile acid-binding pocket of CsSBAT. One inhibitor candidate revealed the least oral toxicity and hepatotoxicity that may enhance its druggability. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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