‘Clean’ or ‘Dirty’ – Just How Selective do Drugs Need to Be?

Giovanni Abbenante; Robert C. Reid; David P. Fairlie

doi:10.1071/CH08186

RESEARCH FRONT

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‘Clean’ or ‘Dirty’ – Just How Selective do Drugs Need to Be?

Giovanni Abbenante ^A , Robert C. Reid ^A and David P. Fairlie ^A ^B

+ Author Affiliations

- Author Affiliations

^A Centre for Drug Design and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane, Qld 4072, Australia.

^B Corresponding author. Email: d.fairlie@imb.uq.edu.au

Dr Giovanni Abbenante received his B.Sc.(Hons) degree from the Department of Chemistry of the University of Adelaide and his Ph.D. degree on the synthesis of GABA_b receptor antagonists from Flinders University in 1992. He undertook postdoctoral studies on the synthesis of ladderanes at Central Queensland University and of HIV-1 protease inhibitors at the University of Queensland. He is a Senior Research Officer in the Centre for Drug Design and Development, Institute for Molecular Bioscience, University of Queensland, with interests in drug design and in the synthesis of protease inhibitors, macrocycles, G protein coupled receptors (GPCR) antagonists, and peptidomimetics.

Dr Robert C. Reid received his B.Sc.(Hons) (1986) and Ph.D. (1990) degrees from the Department of Organic Chemistry, University of Sydney, on the stereospecific total synthesis of natural products with M. J. Crossley. He undertook postdoctoral studies with J. E. Baldwin at the Dyson Perrins Laboratory, Oxford University (1990-93), studying the biosynthesis of penicillins. He is a Senior Research Officer in the Centre for Drug Design and Development, Institute for Molecular Bioscience at the University of Queensland, with research interests in drug design and synthesis, non-peptidic GPCR antagonists, natural products, protease inhibitors, other enzyme inhibitors, and peptidomimetics.

Professor David P. Fairlie has B.Sc.(Hons) (University of Adelaide) and Ph.D. (University of New South Wales) degrees, and did postdoctoral research at Stanford University and the University of Toronto. He has held research and teaching appointments in six Australian universities and led the Chemistry Group in the Centre for Drug Design and Development, at the University of Queensland, since 1991. He has been an Australian Research Council Professorial Fellow and is now an Australian Research Council Federation Fellow. His research interests are in chemical synthesis (organic, medicinal, inorganic); molecular recognition; peptide and protein mimetics; non-peptidic inhibitors of enzymes, including proteases (www.protease.net), and antagonists of GPCRs and other receptors for inflammatory disorders, viral and parasitic infections, cancers, and neurodegenerative diseases. His mechanistic studies have been on chemical reactions, biological processes, disease development, and drug action.

Australian Journal of Chemistry 61(9) 654-660 https://doi.org/10.1071/CH08186
Submitted: 2 May 2008 Accepted: 22 July 2008 Published: 5 September 2008

Abstract

Chemotherapy has developed largely on the basis of searching for chemicals with selective toxicity, targeting a specific step or receptor in a disease process without negatively impacting on normal physiology. The desire for ‘clean’ drugs that act on a single target and thus avoid side effects has led to ever-increasing timeframes for introducing new drugs to humans. This has led to reappraisal of how selective drugs need to be. Examples here of compounds from common drug classes (kinase inhibitors, protease inhibitors, G protein coupled receptors ligands, non-steroidal anti-inflammatory drugs, statins, antibodies) highlight current debate on the merits of target selectivity versus target promiscuity in the development of drugs for inflammation, cancer, cardiovascular, central nervous system and infectious diseases.

Acknowledgement

The Australian Research Council (ARC) and National Health and Medical Research Council provided financial support including an ARC Federation Fellowship to D.P.F.

References

‘Clean’ or ‘Dirty’ – Just How Selective do Drugs Need to Be?

Abstract

Acknowledgement

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