Chemoinformatic Approaches in the Study of Fluralaner and Afoxolaner-mediated Inhibition of l-glutamate-gated Chloride Channels

Douglas Vieira Thomaz, Edson Silvio Batista Rodrigues, Isaac Yves Lopes de Macedo


This work showcased the chemoinformatic study of isoxazoline ectoparasiticides: Fluralaner (FLU) and Afoxolaner (AFO) interactions with l-glutamate-gated chloride channels (3RHW). In order to evaluate inhibition thermodynamics, computational approaches such as molecular docking were employed. Results evidenced that FLU-3RHW highest scoring pose presented lower Gibbs free energy and henceforth, lower Ki values than AFO-3RHW. The findings herein reported suggest therefore that computational methods might be useful to study the thermodynamic features of ectoparasiticides used in veterinary care, what might shed further light on their chemical and pharmacological properties.


ectoparasite; molecular docking; ion channel; HOMO; pharmacodynamics

Full Text:



Gassel, M., Wolf, C., Noack, S., Williams, H., & Ilg, T. (2014). The novel isoxazoline ectoparasiticide fluralaner: Selective inhibition of arthropod γ-aminobutyric acid- and l-glutamate-gated chloride channels and insecticidal/acaricidal activity. Insect Biochemistry and Molecular Biology, 45, 111–124. doi: 10.1016/j.ibmb.2013.11.009

Liu, D., Jia, Z.-Q., Peng, Y.-C., Sheng, C.-W., Tang, T., Xu, L., … Zhao, C.-Q. (2018). Toxicity and sublethal effects of fluralaner on Spodoptera litura Fabricius (Lepidoptera: Noctuidae). Pesticide Biochemistry and Physiology, 152, 8–16. doi: 10.1016/j.pestbp.2018.08.004

Sheng, C.-W., Jia, Z.-Q., Liu, D., Wu, H.-Z., Luo, X.-M., Song, P.-P., … Zhao, C.-Q. (2017). Insecticidal spectrum of fluralaner to agricultural and sanitary pests. Journal of Asia-Pacific Entomology, 20(4), 1213–1218. doi: 10.1016/j.aspen.2017.08.021

Pérez-Sánchez, R., & Oleaga, A. (2017). Acaricidal activity of fluralaner against Ornithodoros moubata and Ornithodoros erraticus argasid ticks evaluated through in vitro feeding. Veterinary Parasitology, 243, 119–124. doi: 10.1016/j.vetpar.2017.06.021

Beugnet, F., Liebenberg, J., & Halos, L. (2015). Comparative efficacy of two oral treatments for dogs containing either afoxolaner or fluralaner against Rhipicephalus sanguineus sensu lato and Dermacentor reticulatus. Veterinary Parasitology, 209(1-2), 142–145. doi: 10.1016/j.vetpar.2015.02.002

Beugnet, F., Liebenberg, J., & Halos, L. (2015). Comparative speed of efficacy against Ctenocephalides felis of two oral treatments for dogs containing either afoxolaner or fluralaner. Veterinary Parasitology, 207(3-4), 297–301. doi: 10.1016/j.vetpar.2014.12.007

Huang, Q.-T., Sheng, C.-W., Jiang, J., Tang, T., Jia, Z.-Q., Han, Z.-J., & Zhao, C.-Q. (2019). Interaction of insecticides with heteromeric GABA-gated chloride channels from zebrafish Danio rerio (Hamilton). Journal of Hazardous Materials, 366, 643–650. doi: 10.1016/j.jhazmat.2018.11.085

Sojka, P. A. (2018). Isoxazolines. Journal of Exotic Pet Medicine, 27(2), 118–122. doi: 10.1053/j.jepm.2018.02.038

Amaro, R. E., Baudry, J., Chodera, J., Demir, Ö., McCammon, J. A., Miao, Y., & Smith, J. C. (2018). Ensemble Docking in Drug Discovery. Biophysical Journal, 114(10), 2271–2278. doi: 10.1016/j.bpj.2018.02.038

Thomaz, D. V., Rodrigues, E. S. B., Machado, F. B., … Macedo, I. Y. L. (2019). Investigation of Cyclobenzaprine Interactions with P450 Cytochromes CYP1A2 and CYP3A4 through Molecular Docking Tools. Path of Science, 5(2), 4001–4006. doi: 10.22178/pos.43-1

Lima Neto, L. F., Barruffini, A. C. C., Machado, F. B., Macedo, I. Y. L., & Thomaz, D. V. (in press). In silico investigation of possible Caffeine interactions with common Inflammation-related targets. Journal of Applied Biology & Biotechnology.

Trott, O., & Olson, A. J. (2009). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31, 455–461. doi: 10.1002/jcc.21334

Case, D. A., Cheatham, T. E., Darden, T., Gohlke, H., Luo, R., Merz, K. M., … Woods, R. J. (2005). The Amber biomolecular simulation programs. Journal of Computational Chemistry, 26(16), 1668–1688. doi: 10.1002/jcc.20290

Salomon-Ferrer, R., Case, D. A., & Walker, R. C. (2012). An overview of the Amber biomolecular simulation package. Wiley Interdisciplinary Reviews: Computational Molecular Science, 3(2), 198–210. doi: 10.1002/wcms.1121

Khorasani, R., & Fleming, P. E. (2016). On calculating HR bond enthalpies using computational data. Computational and Theoretical Chemistry, 1096, 89–93. doi: 10.1016/j.comptc.2016.09.033

Kumar, S. P. (2018). PLHINT: A knowledge-driven computational approach based on the intermolecular H bond interactions at the protein-ligand interface from docking solutions. Journal of Molecular Graphics and Modelling, 79, 194–212. doi: 10.1016/j.jmgm.2017.12.002

Zhang, Q., Bai, P., Zheng, C., Cheng, Y., Wang, T., & Lu, X. (2018). Design, synthesis, insecticidal activity and molecular docking of doramectin derivatives. Bioorganic & Medicinal Chemistry. doi: 10.1016/j.bmc.2018.12.040

Morris, G. M., & Lim-Wilby, M. (2008). Molecular Docking. Molecular Modeling of Proteins, 365–382. doi: 10.1007/978-1-59745-177-2_19

Cosconati, S., Forli, S., Perryman, A. L., Harris, R., Goodsell, D. S., & Olson, A. J. (2010). Virtual screening with AutoDock: theory and practice. Expert Opinion on Drug Discovery, 5(6), 597–607. doi: 10.1517/17460441.2010.484460

Meng, X.-Y., Zhang, H.-X., Mezei, M., & Cui, M. (2011). Molecular Docking: A Powerful Approach for Structure-Based Drug Discovery. Current Computer Aided-Drug Design, 7(2), 146–157. doi: 10.2174/157340911795677602

Lynagh, T., & Lynch, J. W. (2012). Ivermectin binding sites in human and invertebrate Cys-loop receptors. Trends in Pharmacological Sciences, 33(8), 432–441. doi: 10.1016/

Fuse, T., Kita, T., Nakata, Y., Ozoe, F., & Ozoe, Y. (2016). Electrophysiological characterization of ivermectin triple actions on Musca chloride channels gated by l -glutamic acid and γ-aminobutyric acid. Insect Biochemistry and Molecular Biology, 77, 78–86. doi: 10.1016/j.ibmb.2016.08.005

Gielen, M., & Corringer, P.-J. (2018). The dual-gate model for pentameric ligand-gated ion channels activation and desensitization. The Journal of Physiology, 596(10), 1873–1902. doi: 10.1113/jp275100

Burgio, F., Meyer, L., & Armstrong, R. (2016). A comparative laboratory trial evaluating the immediate efficacy of fluralaner, afoxolaner, sarolaner and imidacloprid + permethrin against adult Rhipicephalus sanguineus (sensu lato) ticks attached to dogs. Parasites & Vectors, 9(1). doi: 10.1186/s13071-016-1900-z

Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM


  • There are currently no refbacks.

Copyright (c) 2019 Douglas Vieira Thomaz, Edson Silvio Batista Rodrigues, Isaac Yves Lopes de Macedo

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.