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Drug Discovery Today Citation Classic: The growing impact of click chemistry on drug discovery.

Stephen Carney

Welcome to the first article in Drug Discovery Today Citation Classics. I would say that it is very hard to predict what articles will make citation classic articles, but I suppose that having a Nobel Prize-winning author and a topic of great significance to the field of synthetic medicinal chemistry is a pretty good start.

Since its publication in December 2003, to the time of writing this article in August 2009, it has been cited some 527 times and has never been out of our quarterly top 25 most downloaded articles.

In a nutshell, Click chemistry is a highly reliable modular approach utilising the most efficient and reliable chemical transformations. It has found wide utility throughout drug discovery, but has probably found most benefit  with medicinal chemists in hit and lead generation through combinatorial and target-templated in situ chemistry, as well as in proteomics and DNA research, through the use of bioconjugation reactions.

The approach is best illustrated by the linking reaction involving copper-(I)-catalyzed 1,2,3-triazole formation from azides and terminal acetylenes. This reaction is particularly powerful as a result of its high dependability, complete specificity and the bio-compatibility of the reactants. The triazole possesses other advantages than just passive linkers in that they readily associate with biological targets, through hydrogen bonding and dipole interactions.

Quoting from the original article "The laborious process of lead discovery and optimization has, in recent years, been aided by combinatorial chemistry, to generate collections of test compounds for screening. However, due to the large number of compounds that are involved, combinatorial chemistry is even more dependent than ‘traditional’ synthetic medicinal chemistry on the reliability of the individual reactions used to construct the new network of chemical bonds.

[The Click chemistry process] [1], makes use of a few near-perfect chemical reactions for the synthesis and assembly of specially-designed building blocks. These building blocks have a high built-in energy content that drives a spontaneous and irreversible linkage reaction with complementary sites in other blocks."

In lead optimization, Click chemistry enables rapid SAR profiling, but does not replace existing methods for drug discovery, rather complements and extends them. It works well in conjunction with structure-based medicinal chemistry design and combinatorial chemistry techniques. Using appropriate building blocks, it is possible to produce derivatives or mimics of ‘traditional’ pharmacophores, drugs and natural products [1 and 2]. However, the real power of click chemistry lies in its ability to generate novel structures that might not necessarily resemble known pharmacophores.


Since Click chemistry is both enabled and constrained by its reliance on a few nearly perfect reactions, this, naturally, raises concerns about limitations with respect to chemical diversity. Click chemistry-based searches are fast, however, because they avoid the regions of the ‘1063-universe’ that are difficult to access. They are wide-ranging, owing to the use of strongly driven, highly selective reactions of broad scope, allowing a much greater diversity of block structures to be used. Thus, the premise of click chemistry would be that it allows makes greater diversity achievable with fewer reactions, because it is not the number of reactions that is important, but the tolerance of those reactions to variations in the nature of their components.

Drug Discovery Today Citation Classic

The growing impact of click chemistry on drug discovery

Drug Discovery Today (2003) 8(24), 1128-1137

By Hartmuth C. Kolb and K. Barry Sharpless

1 Kolb, H.C. et al. (2001) Click chemistry: diverse chemical function from
a few good reactions. Angew. Chem. Int. Ed. Engl. 40, 2004–2021

2 Bemis, G.W. and Murcko, M.A. (1996) The properties of known drugs.
1. Molecular frameworks. J. Med. Chem. 39, 2887–2893


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