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.
Key words:
Epidermal growth factor receptor, tyrosine kinase,
tarceva,
non-small cell lung cancer, ovarian cancer,
molecular
modeling
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