Miranda-Miranda, E.; Cossío-Bayúgar, R.; Trejo-Castro, L.; Aguilar-Díaz, H. Triclabendazole-Binding Pocket Identified in Fasciola hepatica Carboxylesterase B. Preprints2023, 2023090347. https://doi.org/10.20944/preprints202309.0347.v1
APA Style
Miranda-Miranda, E., Cossío-Bayúgar, R., Trejo-Castro, L., & Aguilar-Díaz, H. (2023). Triclabendazole-Binding Pocket Identified in <em>Fasciola hepatica </em>Carboxylesterase B. Preprints. https://doi.org/10.20944/preprints202309.0347.v1
Chicago/Turabian Style
Miranda-Miranda, E., Lauro Trejo-Castro and Hugo Aguilar-Díaz. 2023 "Triclabendazole-Binding Pocket Identified in <em>Fasciola hepatica </em>Carboxylesterase B" Preprints. https://doi.org/10.20944/preprints202309.0347.v1
Abstract
The expression of the Fasciola hepatica Carboxylesterase type B (CestB) gene is induced in response to the anthelmintic triclabendazole (TCBZ), resulting in a significant increase in enzymatic specific activity. Furthermore, the amino acid sequence of CestB exhibits variations that could lead to substantial amino acid substitutions at the ligand-binding site. These substitutions have the potential to affect the interaction between the ligand and the protein, as well as the catalytic properties of the enzyme. The objective of this study was to identify new CestB polymorphisms in TCBZ-resistant parasites using 3D modeling against the metabolically oxidized form of the anthelmintic TCBZSOX. Our aim was to observe the formation of TCBZSOX-specific binding pockets that could potentially explain the resistance to anthelmintic agents. We identified a CestB polymorphism in a TCBZ-resistant strain of parasites exhibiting three radical amino acid substitutions at positions 147, 215, and 243, resulting in the formation of a TCBZSOX-affinity pocket capable of binding the anthelmintic drug. Additionally, our 3D modeling analysis revealed that these amino acid substitutions also had an impact on the configuration of the CestB catalytic site, affecting the enzyme's interaction with chromogenic carboxylic ester substrates and altering its catalytic properties; however, the identified TCBZSOX-binding pocket was located far from the enzyme's catalytic site, making the enzymatic hydrolysis of TCBZSOX theoretically impossible. Nonetheless, the increased affinity for the anthelmintic may explain a drug-sequestration type of anthelmintic resistance and lays the foundation for the development of a molecular diagnostic tool for identifying anthelmintic resistance in F. hepatica.
Keywords
Fasciola hepatica; triclabendazole; anthelmintic-resistance; amino acid-substitution; binding-pocket; ligand-protein docking; protein 3D modeling.
Subject
Medicine and Pharmacology, Tropical Medicine
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
