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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