10- Metabolism of niclosamide – a molecular modelling analysis

Fazlul Huq

Discipline of Biomedical Science, School of Medical Sciences, Faculty of Medicine, The University of Sydney, Australia. Telephone: +61 2 9351 9522  Fax: +61 2 9351 9520 E-mail : F.Huq@usyd.edu.au.

Abstract

Niclosamide is a restricted-use pesticide that has been successfully used for more than 40 years to control sea lampreys in streams tributary to the Great Lakes. Itis also used to kill golden apple snail which is a major pest of rice. Despite its general use, niclosamide is found to be toxic to several aquatic organisms. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that niclosamide and its metabolites differ in their LUMO-HOMO energy differences and hence kinetic lability. TCFNA has the smallest LUMO-HOMO energy difference and hence the greatest reactivity. It has also a lower solubility in water and possibly a lower thermodynamic stability. These properties may make TCFNA to be a toxic and mutagenic metabolite. The molecular surface of TCFNA is found to possess significant amount of electron-deficient region so that it may be subject to nucleophilic attack by glutathione and nucleobases in DNA. Reaction with glutathione induces cellular toxicity associated with glutathione depletion whereas oxidation of nucleobases in DNA causes DNA damage.

Key words: Niclosamide, salicylanilide, sea lamprey, molecular modelling

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