Molecular docking and dynamics as a tool to study benzimidazole resistance in helminths: A scoping review

Abstract

Background: Benzimidazole (BZ) resistance remains an emerging grave concern in helminths of public and veterinary health concerns. Resistance against BZ drugs is due to mutations that change the amino acid comprising the β-tubulin protein, which negatively affects its interactions with BZ drug molecules. Several in silico modeling studies have been published to decipher the precise mechanism of BZ resistance, but inconsistencies on the resistance consequence mutations confer and the effect of different BZ ligands have led to further confusion regarding the exact mechanism of resistance. Hence, this scoping review was done to unravel the mechanism of BZ resistance based on published research on molecular docking and dynamics. Methods: A scoping review was conducted in ScienceDirect, MEDLINE via PubMed and Scopus using the search term “Benzimidazole Resistance AND Beta Tubulin AND Molecular Docking”. A total of 37 hits were recovered and from these 6 were included after selection, inclusion, and risk of bias assessment. Results: The six research papers included in this review studied several helminth species: Haemonchus conturtos, Trichinella spiralis, Ancylostoma duodenale, Ancylostoma caninum, Ancylostoma ceylanicum, Necator americanus, Trichuris trichiura, Trichuris suis, Anisakis simplex, Ascaris suum, Ascaridia galli, Parascaris equorum, Toxocara canis, and Fasciola hepatica. The benzimidazole resistance-associated mutations studied included F167Y (TTC, TTT → TAC, TAT), E198A (GAG, GAA → GCG, GCA), and F200Y (TTC, TTT → TAC, TAT). The results show that the E198A can markedly reduce the binding affinity of BZ ligand-β-tubulin interactions. The F167Y and F200Y also showed a similar effect that could vary based on the helminth species. The F200Y mutation can alter the conformation of the β-tubulin active site, negatively affecting drug binding. Conclusion: While the impact of these mutations can vary depending on the specific helminth species and the BZ drug involved, the overall findings highlight the importance of targeting these residues for the development of novel anthelmintic strategies to address emerging drug resistance.