Molecular Modelling Analysis of the Metabolism of Tegaserod
Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that TGS and its major metabolites MIM, MIMA, MIMAG, ODMTGS, TGSG1, TGSG2 and TGSG3 have LUMO-HOMO energy differences ranging from 4.4 to 5.0 eV from DFT calculations so that they all would be moderately inert kinetically. The molecular surfaces of TGS 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. The molecular surface of none of the compounds is found to abound in electron-deficient (blue) regions so that the compounds may not react readily with cellular nucleophiles such as glutathione and nucleobases in DNA. This means that none of the compounds may cause significant oxidative stress associated with glutathione depletion or DNA damage associated with oxidation of nucleobases.
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