Molecular Modelling Analysis of the Metabolism of Troglitazone
In this study, molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) have been carried out for troglitazone (TGZ) and its metabolites with the aim of obtaining information on their relative toxicity. The results of the analyses show that TGZ and its metabolites have LUMO-HOMO energy differences ranging from 4.1 to 4.9 eV from DFT calculations except TGZQ which has much lower value of 2.69 eV. The values suggest although TGZ and most of its metabolites would be kinetically inert, the metabolite TGZQ would be highly labile. The molecular surfaces of TGZ and its metabolites are found to abound in neutral (green) and electron-rich (red and yellow) regions so that the compounds may undergo lyophilic and electrophilic attacks. TGZ and all its metabolites also possess some electron-deficient regions so that they may be subject to nucleophilic attacks by glutathione and nucleobases as well. However, the rates of such adverse reactions are expected to be low for TGZ and its metabolites except in the case of the highly labile metabolite TGZQ.
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