1-   Molecular modelling analysis of the metabolism of trilostane

Fazlul Huq

Discipline of Biomedical Science, Faculty of Medicine, The University of Sydney, PO Box 170 East Street C42, Lidcombe, NSW, Australia.

Phone:+61 2 93519522; Fax: +61 2 9351 9520

Email: F.Huq@usyd.edu.au

Trilostane (TR) is an orally active synthetic steroid used for the treatment of advanced breast cancer. It can block the synthesis of steroids, making it useful for the treatment of hormone-dependent mammary cancers in post-menopausal women where its main action is the selective inhibition of 3b-hydroxysteroid dehydrogenase which is a key enzyme necessary for the production of glucocorticoids, mineralocorticoids and androgens. Not much is known about the side effects of TR and its metabolites. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that TR and all its metabolites have large LUMO-HOMO energy differences so that they would be kinetically inert. Thus, although the molecules have some electron-deficient regions on their surface so that they could potentially react with glutathione and nucleobases in DNA, the high kinetic inertness of the molecules is believed to provide protection against such adverse reactions.

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