7. Molecular
Modelling Analysis of The Metabolism of Strychnine
Fazlul Huq and Fehmida Fasim
Discipline of Biomedical Science, Faculty of Medicine, The
University of Sydney
Address reprint requests and correspondences to:
A/Prof Fazlul Huq, Discipline of Biomedical Science,
Faculty of Medicine, C42, The University of Sydney,
PO Box 170, Lidcombe, NSW 1825, Australia.
Telephone: +61 2 9351 9522 Fax: +61 2 9351 9520
E-mail :
f.huq@usyd.edu.au.
Abstract: Molecular modelling analyses based on molecular mechanics,
semi-empirical (PM3) and DFT (at B3LYP/6-31G* level)
calculations show that strychnine and its metabolites differ
in their kinetic lability with LUMO-HOMO energy differences
ranging from 4.55 to 5.40 eV from DFT calculations. The
metabolites ST-N-OX and 21,22-DEHST are found to have the
lowest LUMO-HOMO energy differences and hence are expected
to be most labile. The molecular surfaces of strychnine,
ST-EPOX, ST-N-OX and 11,12-DEHST are found to abound in
electron-deficient regions so that they may react with
cellular nucleophiles such as reduced form of glutathione
and nucleobases in DNA, thus causing depletion of
glutathione and oxidation of nucleobases in DNA
respectively. The depletion of cellular glutathione level is
expected to induce cellular toxicity due to oxidative stress
whereas the oxidation of nucleobases would cause DNA damage.
Key words: Strychnine, alkaloid, strychnos nux vomica,
glycine receptor antagonist, pesticide, molecular modelling
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