Molecular Modelling Analysis of the Metabolism of Enoxacin
Enoxacin (ENX) is an orally active fluorinated quinolone antimicrobial agent that has strong activity against both gram-positive and gram-negative bacteria. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that ENX and its metabolites have moderately large LUMO-HOMO energy differences so that neither ENX nor any its metabolites is expected to be extremely inert and highly labile. The molecular surfaces of the compounds are found to possess neutral (green) and negative (yellow and red) and electron-deficient (blue) regions so that they may be subject to lyophilic, electrophilic and nucleophilic interactions. Nucleophilic attack may be due to glutathione and nucleobases in DNA resulting into glutathione depletion and oxidation of nucleobases. Depletion of glutathione depletion would induce oxidative stress and hence cellular toxicity whereas oxidation of nucleobases in DNA would cause DNA damage. Some what higher reactivity of ENX coupled with the presence of a larger amount of electron-deficient regions may mean that the consequences of such adverse reactions would be greater in the case of the parent drug than in any of the metabolites.
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