7- Molecular Modelling Analysis of The Metabolism of Gefitinib

                                  Fazlul Huq

                   Discipline of Biomedical Science, Faculty of Medicine, The University of Sydney

The University of Sydney, PO Box 170 75 East Street Lidcombe NSW 1825, Australia.

Phone: 061 2 9351 9522; Fax: 061 2 9351 9520, e-mail: f.huq@usyd.edu.au

Abstract

Gefitinib (GF) is an orally active inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) involved in signal transduction processes and implicated in proliferation and maintenance of cancer cells. It inhibits epidermal growth factor-stimulated tumour growth when administered orally to mice bearing a range of human tumour xenografts. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that neither GF nor any of its metabolites is highly labile or extremely inert kinetically. The metabolite M605211 although marginally less reactive than the metabolite M387783, is found to abound most in electron-deficient regions so that it can be subject to nucleophilic attack by glutathione and nucleobases in DNA. The reaction with glutathione can cause glutathione depletion thus inducing oxidative stress and cellular toxicity whereas that the oxidation of nucleobases in DNA can cause DNA damage.

Key words: Gefitinib, epidermal growth factor receptor, tyrosine kinase, antitumour activity, molecular modelling

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