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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