|
1- Molecular modelling analysis of
the metabolism of zileuton
Fazlul Huq
Discipline of Biomedical Science, Faculty of Medicine, The University
of Sydney,
E-mail :
F.Huq@usyd.edu.au.
Dr. Fazlul Huq, Discipline of Biomedical Science, Faculty of Medicine,
C42, The University of Sydney,
PO Box 170, Lidcombe, NSW 1825, Australia.
Telephone:+61 2 9351 9522, Fax: +61 2 9351 9520
E-mail:F.Huq@usyd.edu.au.
Abstract
Zileuton (ZT) is a potent and selective inhibitor of 5-lipooxygenase
that converts arachidonic acid to
5-hydroperoxy-eicosa-6,8,11,14-tetranoic acid (5-HPETE) in a pathway
that leads to the production of leukotrienes. Inhibition of
leukotriene synthesis has many potentially therapeutic benefits for
conditions such as asthma, rheumatoid arthritis, psoriasis and
inflammatory bowel disease in which synthesis of leukotriene is
elevated. The use of ZT is however associated with liver toxicity
limiting its clinical usefulness. There is evidence to suggest that
this toxicity is due to its biotransformation producing cytotoxic
metabolites. Molecular modelling analyses based on molecular
mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level)
calculations show that ZT and its metabolites differ in their kinetic
lability. The metabolites M1 and M4 are found to have the lowest
LUMO-HOMO energy differences and hence are expected to be most labile.
The molecular surfaces of M1 and M4 are also found to abound in
electron-deficient regions so that they can react readily with
cellular nucleophiles such as the reduced form of glutathione and
nucleobases in DNA, causing glutathione depletion and DNA damage
respectively. The depletion of glutathione level will induce cellular
toxicity associated with the resulting oxidative stress. Another
likely toxic metabolite is M6. Although M6 is expected to be less
reactive than metabolites M1 and M4, its higher lipid solubility and
lower clearance rate and the presence of electron-deficient regions on
its molecular surface as well would make M6 to be highly toxic.
Key words:
Insomnia, leukotrienes, asthma, arthritis, arachidonic acid, molecular
modelling
<<< |
