3- Molecular modelling analysis of the metabolism of mifepristone

 Fazlul Huq

Discipline of Biomedical Science, Faculty of Medicine, The University of Sydney

 Address reprint requests and correspondences to:

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.

 Key words: Mifepristone, RU486, steroid, abortion, molecular modelling

Abstract

RU486 is a synthetic 19-nor-steroid that binds strongly to progesterone as well as glucocorticoid receptors, thus acting as an antagonist to progestational and glucocorticoid functions. Currently RU486 is used as an abortifacient in France, UK, Sweden and China. The side effects of RU486 include abdominal pain, cramping, nausea, vomiting, bleeding, and delay in onset of the next menstrual cycle. Molecular modelling analyses based on molecular mechanics, semi-empirical and DFT (at B3LYP/6-31G* level) calculations show that RU486 and its metabolites are all fairly inert kinetically except FMFP which is much more labile. The presence of some electron-deficient regions on the molecular surfaces of RU486 and all its metabolites indicates that none of the compounds may be totally immune to nucleophilic attack. However, the rates of such adverse reactions are expected to be low for RU486 and all its metabolites except for the kinetically labile metabolite FMFP so that FMFP could induce cellular toxicity associated with glutathione depletion and DNA damage from oxidation of nucleobases.

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