Molecular Modelling Analysis of the Metabolism of Eszopiclone
Eszopiclone (ESZ) is a recently introduced drug to treat insomnia. 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 insight into toxicity of ESZ and its metabolites. The results of the study show that both ESZ and its metabolites NDMESZ and ESZNO have small LUMO-HOMO energy differences, indicating that the compounds would be kinetically labile with ESZNO being most reactive. The molecular surfaces of ESZ, NDMESZ and ESZNO are found to posses significant amounts of electron-deficient regions so that the compounds, especially ESZNO, can react readily 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 associated with oxidation of nucleobases.
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