Haemonchus contortus is a small ruminant gastrointestinal parasitic nematode that rapidly develops resistance to many anthelmintic classes, such as benzimidazoles (eg albendazole). Benzimidazoles are microtubule inhibitors that disrupt the dynamic balance between microtubules and free heterodimeric tubulin. To uncover the molecular mechanism underlying the inhibition of H. contortus microtubule polymerization by benzimidazoles and the resistance caused by polymorphisms, we generated structural models of H. contortus tubulin (TBA-1/TBB-1) wild-type (WT), F167Y, E198A and F200Y variants for in silico modeling in the presence of albendazole. Modeled tubulin dimers were post-analyzed using MM/GBSA, resulting in similar ΔGbind negative values, suggesting that albendazole binds to the β-tubulin subunit despite polymorphisms. The analysis also revealed secondary structure changes at β-sheet 4 (S4), S6, S8, S9, α-helix 7 (H7) and H8 of the β-tubulin model when albendazole was bound. These changes restrict the movement of the intradimer interface of the α-/β-tubulin heterodimer. We hypothesize that albendazole inhibits the transition of the curved to the straight heterodimer conformation. The microtubule ends shrink by the inhibition of the transition. Also, albendazole connects β4S and β6S in WT+ albendazole, resulting in compaction. Furthermore, we identified a hydrogen bond in F167Y (β: Y167:HH – β: E198:OE1) and F200Y (Y200:HN – β: T199:OG1) variants of the tubulin dimer. These hydrogen bonds could reduce the negative partial charge of E198, which is critical for interacting with albendazole. We postulate that charge modulation or an amino acid change of E198 prevent its interaction with albendazole, leading to resistance.
