6- Molecular modelling analysis of the metabolism of diflunisal

 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: Diflunisal, NSAID, arthritis, toxicity, glutathione, molecular modelling

Abstract

Diflunisal (DF) is a lipophilic derivative of salicylic acid belonging to the class of compounds called NSAIDs that are widely used to relieve pain and inflammation in rheumatoid and osteoarthritis. However, NSAIDs frequently cause gastrointestinal (GI) toxicity resulting into ulceration, bleeding and perforation. NSAIDs including DF have been demonstrated to bind covalently to intra- and extracellular proteins. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that the diketonic species DF-DK that may be formed from oxidation of DF would be highly electrophilic abounding in electron-deficient regions on its molecular surface and extremely reactive so that it can readily cause depletion of cellular glutathione and oxidation of nucleobases in DNA. However, no such metabolite has been detected in the metabolism of DF.

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