Recent applications of click chemistry in drug discovery

ABSTRACT

Introduction: Click chemistry has been exploited widely in the past to expedite lead discovery and optimization. Indeed, Copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry is a bioorthogonal reaction of widespread utility throughout medicinal chemistry and chemical biology.

Areas covered: The authors review recent applications of CuAAC click chemistry to drug discovery based on the literature published since 2013. Furthermore, the authors provide the reader with their expert perspectives on the area including their outlook on future developments.

Expert opinion: Click chemistry reactions are an important part of the medicinal chemistry toolbox and offer substantial advantages to medicinal chemists in terms of overcoming the limitations of useful chemical synthesis, increasing throughput, and improving the quality of compound libraries. To explore new chemical spaces for drug-like molecules containing a high degree of structural diversity, it may be useful to merge the diversity-oriented synthesis and ‘privileged’ substructure-based strategy with bioorthogonal reactions using sophisticated automation and flow systems to improve productivity. Large compound libraries obtained in this way should be of great value for the discovery of bioactive compounds and therapeutic agents.

KEYWORDS:

• CuAAC
• Click chemistry
• Medicinal chemistry
• Drug design
• Bioorthogonal reactions

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article Highlights

• Click chemistry has been exploited widely to expedite lead discovery and optimization.

• Copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry is the prime example of current bioorthogonal reactions.

• The combination of CuAAC click-chemistry and in situ screening is a powerful methodology for identifying lead compounds.

• Tethering in situ click chemistry can generate novel lead compounds even from fragments with weak target-binding affinity.

• The potential of bioorthogonal reactions for drug discovery has only just started to be explored.

Additional information

Funding

The authors have received financial support from the National Natural Science Foundation of China (NSFC No. 81573347), the Young Scholars Program of Shandong University (YSPSDU No. 2016WLJH32), China’s Postdoctoral Science Foundation (2018M640641), the Fundamental Research Funds of Shandong University (No. 2017JC006), Key Project of the National Natural Science Foundation of China (NSFC) for International Cooperation (No. 81420108027), and the Key Research and Development Project of Shandong Province (No. 2017CXGC1401).