A Molecular Modelling Analysis of the Metabolism of Mexiletine
In this study, molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations have been carried out to obtain information on the toxicity of mexiletine (MEX) and its metabolites. The results of the analyses show that MEX and its metabolites have moderately large to large LUMO-HOMO energy differences ranging from 5.4 to 6.4 eV indicating that the compounds would be inert kinetically, with the parent drug being most inert. The molecular surface of one of the metabolites namely HMMEX is found to possess significant amount of positively charged electron-deficient regions so that it may be subject to nucleophilic attacks by glutathione and nucleobases in DNA, thus causing cellular toxicity due to glutathione depletion and DNA damage due to oxidation of nucleobases. However, because of kinetic inertness of the molecule, the rate of such adverse reactions is expected to be low.
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