2- Molecular modeling analysis of the metabolism of tarceva

Fazlul Huq

Discipline of Biomedical Science, School of Medical Sciences,

Faculty of Medicine,The University of Sydney

Tarceva is an orally active quinazoline derivative that binds to ATP pocket of the EGFR and inhibits its autophosphorylation. When used alone, it shows activity in non-small cell lung, head and neck and ovarian cancers and has been approved in the United States and Switzerland for treatment against locally advanced or metastatic non-small cell lung cancer that represents a growing global problem and remains a therapeutic challenge. The drug is extensively metabolized in humans with less than 2% excreted as the unchanged drug. Three major biotransformation pathways are O-demethylation of the side chains followed by oxidation to carboxylic acid, oxidation of the acetylene moiety and the hydroxylation of the aromatic ring. In plasma, the unchanged drug represents the major circulating component whereas the pharmacologically active metabolite M14 produced from O-demethylation accounts for only about 5%. A number of phase I metabolites are excreted as glucuronides or sulfates. Molecular modeling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that tarceva and its metabolites have moderately large LUMO-HOMO energy differences so that neither tarceva nor any its metabolites is expected to be highly inert and extremely labile. The molecular surfaces of the compounds are found to abound in neutral (green) and negative (yellow and red) regions so that they may undergo lyophilic interaction and may be subject to electrophilic attack. In addition, all the compounds are found to possess some electron-deficient (blue) regions so that they may also be subject to nucleophilic attack e.g. that by glutathione and nucleobases in DNA. Glutathione depletion will induce oxidative stress and hence cellular toxicity whereas oxidation of nucleobases in DNA would cause DNA damage. However, the moderate kinetic inertness of the molecules means that the rates of such adverse reactions may not be too high or too low.

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