2- Molecular modelling analysis of the metabolism of andrographolide

Fazlul Huq and Nurhanan Murni Yunos

Discipline of Biomedical Science, School of Medical Sciences, Faculty of Medicine, Cumberland Campus, C42, The University of Sydney, Lidcombe, NSW, Australia.

Phone: +61 2 9351 9522; Fax: +61 2 9351 9520 Email: F.Huq@usyd.edu.au

Andrographolide (ANDRO) is believed to possess hepatoprotective property, anti-inflammatory and antimicrobial activity including that against HIV, and ability to assist antiplatelet aggregation. ANDRO has been widely used in clinic for the treatment of a number of ailments including fever, cold, malaria, inflammation and diarrhoea and has shown antitumour activities both in vitro and in vivo breast cancer tumour models. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that ANDRO and its metabolites have moderately large to large LUMO-HOMO energy differences ranging from 4.6 to 5.7 eV, indicating that the compounds would be moderate to highly inert kinetically. The molecular surfaces of all the compounds are found to abound in neutral green and electron-rich red and yellow regions so that the compounds may be subject to lyophilic and electrophilic attacks. The presence of electron-rich regions renders antioxidant attributes to the molecules, thus providing an explanation for the hepetoprotective role played by andrographolide. Some of the metabolites are also found to possess electron-deficient blue regions so that they may be subject to nucleophilic attacks. Nucleophilic attacks may be due to glutathione and nucleobases in DNA as a result of which depletion of glutathione and oxidation of nucleobases in DNA may occur. The former would induce oxidative stress and hence cellular toxicity whereas the latter would cause DNA damage. However, because of kinetic inertness of the molecules, the rates of such adverse reactions are expected to be low unless speeded up enzymatically.

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