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Protein Modelling and Molecular Docking Analysis of Fasciola hepatica β-Tubulin’s Interaction Sites, with Triclabendazole, Triclabendazole Sulphoxide and Triclabendazole Sulphone

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Abstract

Purpose

Fasciola hepatica is a globally distributed trematode that causes significant economic losses. Triclabendazole is the primary pharmacological treatment for this parasite. However, the increasing resistance to triclabendazole limits its efficacy. Previous pharmacodynamics studies suggested that triclabendazole acts by interacting mainly with the β monomer of tubulin.

Methods

We used a high-quality method to model the six isotypes of F. hepatica β-tubulin in the absence of three-dimensional structures. Molecular dockings were conducted to evaluate the destabilization regions in the molecule against the ligands triclabendazole, triclabendazole sulphoxide and triclabendazole sulphone.

Results

The nucleotide binding site demonstrates higher affinity than the binding sites of colchicine, albendazole, the T7 loop and pβVII (p < 0.05). We suggest that the binding of the ligands to the polymerization site of β-tubulin can lead a microtubule disruption. Furthermore, we found that triclabendazole sulphone exhibited significantly higher binding affinity than other ligands (p < 0.05) across all isotypes of β-tubulin.

Conclusions

Our investigation has yielded new insight on the mechanism of action of triclabendazole and its sulphometabolites on F. hepatica β-tubulin through computational tools. These findings have significant implications for ongoing scientific research ongoing towards the discovery of novel therapeutics to treat F. hepatica infections.

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Data Availability

The data that generated this publication is available if required by this journal. All the data is freely accessible online, the models are in the repository of protein models reported in the results.

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Acknowledgements

P.O.F. is grateful for the support of ANID-PCHA/2017/21170159.

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Authors and Affiliations

  1. Laboratory of Molecular Immunoparasitology, Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Temuco, Chile

    Pamela Olivares-Ferretti & Flery Fonseca-Salamanca

  2. Chemical Engineering Department, Faculty of Engineering and Science, Universidad de La Frontera, Temuco, Chile

    Jorge F. Beltrán

  3. Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Avenida Francisco Salazar 01145, 4811230, Temuco, Chile

    Luis A. Salazar

  4. Preclinical Sciences Department, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile

    Flery Fonseca-Salamanca

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  3. Luis A. Salazar
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  4. Flery Fonseca-Salamanca
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by PO-F and JFB. The first draft of the manuscript was written by PO-F and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Flery Fonseca-Salamanca.

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Olivares-Ferretti, P., Beltrán, J.F., Salazar, L.A. et al. Protein Modelling and Molecular Docking Analysis of Fasciola hepatica β-Tubulin’s Interaction Sites, with Triclabendazole, Triclabendazole Sulphoxide and Triclabendazole Sulphone. Acta Parasit. 68, 535–547 (2023). https://doi.org/10.1007/s11686-023-00692-z

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