In situ click chemistry: a powerful means for lead discovery

Abstract

Combinatorial chemistry and parallel synthesis are important and regularly applied tools for lead identification and optimisation, although they are often accompanied by challenges related to the efficiency of library synthesis and the purity of the compound library. In the last decade, novel means of lead discovery approaches have been investigated where the biological target is actively involved in the synthesis of its own inhibitory compound. These fragment-based approaches, also termed target-guided synthesis (TGS), show great promise in lead discovery applications by combining the synthesis and screening of libraries of low molecular weight compounds in a single step. Of all the TGS methods, the kinetically controlled variant is the least well known, but it has the potential to emerge as a reliable lead discovery method. The kinetically controlled TGS approach, termed in situ click chemistry, is discussed in this article.

Keywords::

• acetylcholinesterase
• carbonic anhydrase
• DNA-templated reactions
• fragment-based lead discovery
• HIV protease
• in situ click chemistry
• target-guided synthesis
• triazole

Acknowledgements

The authors wish to thank L Malmgren for the helpful discussions and editorial help. The authors also thank the American Cancer Society (RM), Sponsored Research at the University of South Florida (RM), the National Institute of General Medical Sciences, National Institute of Health (KBS) and the WM Keck Foundation (KBS) for research funding.

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