ReviewThe growing impact of click chemistry on drug discovery
Section snippets
The click chemistry approach
Click chemistry serves as a guiding principle in the quest for function: the search must be restricted to molecules that are easy to make. Focusing on lead discovery, this strategy provides a means for the rapid exploration of the chemical universe. For lead optimization, it enables rapid SAR profiling, through generation of analog libraries. Click chemistry does not replace existing methods for drug discovery, but rather, it complements and extends them. It works well in conjunction with
Click chemistry and drug discovery
Click chemistry is being used increasingly in biomedical research, ranging from lead discovery and optimization, to tagging of biological systems, such as proteins, nucleotides and whole organisms. The potential of this approach is highlighted here, by reviewing several early applications.
Click chemistry and bioconjugation
In vivo and in vitro bioconjugation applications benefit from the unprecedented reliability of the copper-catalyzed azide–acetylene union, the inertness of the reactants under physiological conditions, and the mild reaction conditions.
Conclusions
In summary, click chemistry has proven to be a powerful tool in biomedical research, ranging from combinatorial chemistry and target-templated in situ chemistry for lead discovery, to bioconjugation strategies for proteomics and DNA research. Of the various click chemistry reactions that are available to us, the union of azides and acetylenes to give triazoles deserves special recognition. Azides and acetylenes are stable across a broad range of organic reaction conditions and in biological
Acknowledgements
We are grateful to our colleagues M.G. Finn, Valery Fokin and Paul Carlier for advice and helpful discussions. We also thank Pascale Marchot, Yves Bourne and Palmer Taylor for allowing us to include the X-ray crystallographic results on the AChE inhibitors before publication, and Chi-Huey Wong for giving permission to discuss the HIV-protease work. Many thanks also to Paul Richardson and Zhi-Cai Shi of Lexicon Pharmaceuticals for being among the pioneers of click chemistry.
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