Molecular Modelling Analysis of the Metabolism of Thiabendazole
Thiabendazole (TBZ) is a broad-spectrum anthelmintic that is effective against gastrointestinal nematodes in ruminants and lungworms in sheep. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that TBZ and its metabolites have moderately large LUMO-HOMO energy differences except 5K-TBZ which has a much smaller value. The results indicate that generally TBZ and its metabolites would be fairly inert kinetically except 5K-TBZ which would be highly labile. The molecular surfaces of TBZ and its metabolites are found to possess neutral (green) and negative (yellow and red) and some electron-deficient (blue) regions so that they may be subject to lyophilic, electrophilic and nucleophilic interactions. Terminal metabolite TBZ-5S is found to abound most in electron-rich negative regions so that it may be most subject to electrophilic attack whereas the most reactive metabolite 5K-TBZ is found to abound most in electron-deficient regions so that it can be most subject to nucleophilic attack. Nucleophilic attack to the electron-deficient sites may be due to glutathione and nucleobases in DNA resulting into glutathione depletion and oxidation of nucleobases. Depletion of glutathione depletion would induce oxidative stress and hence cellular toxicity whereas oxidation of nucleobases in DNA would cause DNA damage.
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