Molecular Modelling Analysis of the Metabolism of Aniracetam
Aniracetam (ACM) is a pyrrolidinone-type cognition enhancer that has been used in the treatment of behavioural and psychological symptoms of dementia following stroke and Alzheimer’s disease. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that both ACM and its major metabolites have LUMO-HOMO energy differences ranging from 4.89 to 7.4 eV, indicating that the compounds would all be kinetically inert with SD being the most inert and the parent drug being the least inert one. The molecular surface of ACM is found to posses significant amounts of electron-deficient regions so that it 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. However, because ACM is expected to be to some extent kinetically inert, the rates of such adverse reaction are expected to be low unless speeded up enzymatically.
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