Molecular Modelling Analysis of the Metabolism of Zolpidem
Zolpidem (ZP) is a new orally active sleep inducer belonging to the class of compounds known as imidazopyridine. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that parent drug and all its metabolites have moderately large LUMO-HOMO energy differences so that none is expected to be highly labile kinetically. The molecular surface of ZP is found to abound in electron-deficient regions so that it can react with cellular nucleophiles such as glutathione and nucleobases in DNA, thus inducing cellular toxicity and causing DNA damage respectively. However, because of kinetic inertness, the rates of such adverse reaction may be low unless speeded up enzymatically. Increased incidence of nausea and vomiting associated with higher doses of ZP may be due to the parent drug rather than any of its metabolites.
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