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Molecular modelling analyses of the metabolism of darifenacin
Fazlul Huq
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
Abstract
Darifenacin (DFC) is a novel muscarinic M3 selective antagonist
used for the once-daily oral treatment of urinary incontinence
and overactive bladder. Molecular modelling analyses based on
molecular mechanics, semi-empirical (PM3) and DFT (at
B3LYP/6-31G* level) calculations show that DFC and its
metabolites have large LUMO-HOMO energy differences ranging from
5.2 to 5.6 eV, indicating that DFC and all its metabolites would
be kinetically inert. The molecular surfaces of DFC and its
metabolites 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. None of the
compounds abounds in electron-deficient (blue) regions so that
none may experience any significant nucleophilic attacks such as
those due to glutathione and nucleobases in DNA. This means that
DFC and its metabolites may not induce cellular toxicity that
results from glutathione depletion and may not cause DNA damage
that results from oxidation of nucleobases.
Key words: Darifenacin, urinary incontinence, overactive
bladder, M3 antagonist, molecular modelling
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