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Journal of Pharmacology and Toxicology

Year: 2008  |  Volume: 3  |  Issue: 1  |  Page No.: 11 - 19

Molecular Modelling Analysis of the Metabolism of Methimazole

Fazlul Huq


Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that MET and its major metabolites have LUMO-HOMO energy differences ranging from 4.1 to 6.7 eV from DFT calculations, indicating that they would vary significantly in their kinetic inertness. The molecular surfaces of MET, MTU, MET-EPO and GLX are found to possess significant amounts of electron-deficient regions so that they can react with cellular nucleophiles such as glutathione and nucleobases in DNA, thus causing depletion of glutathione and oxidation of nucleobases. The former would induce cellular toxicity due to oxidative stress and the latter would cause DNA damage. The rates of such adverse reactions are expected to be significant for GLX which would be moderately labile kinetically. This means that the toxicity due to MET may be mediated via the formation of GLX although the parent drug itself may also be responsible for toxicity if the rates of its reactions with glutathione and nucleobases in DNA are speeded up enzymatically.

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