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Issue 2, 2021
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Fragment-based covalent ligand discovery

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Targeted covalent inhibitors have regained widespread attention in drug discovery and have emerged as powerful tools for basic biomedical research. Fueled by considerable improvements in mass spectrometry sensitivity and sample processing, chemoproteomic strategies have revealed thousands of proteins that can be covalently modified by reactive small molecules. Fragment-based drug discovery, which has traditionally been used in a target-centric fashion, is now being deployed on a proteome-wide scale thereby expanding its utility to both the discovery of novel covalent ligands and their cognate protein targets. This powerful approach is allowing ‘high-throughput’ serendipitous discovery of cryptic pockets leading to the identification of pharmacological modulators of proteins previously viewed as “undruggable”. The reactive fragment toolkit has been enabled by recent advances in the development of new chemistries that target residues other than cysteine including lysine and tyrosine. Here, we review the emerging area of covalent fragment-based ligand discovery, which integrates the benefits of covalent targeting and fragment-based medicinal chemistry. We discuss how the two strategies synergize to facilitate the efficient discovery of new pharmacological modulators of established and new therapeutic target proteins.

Graphical abstract: Fragment-based covalent ligand discovery

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Article information

04 Dec 2020
20 Jan 2021
First published
09 Feb 2021

This article is Open Access

RSC Chem. Biol., 2021,2, 354-367
Article type
Review Article

Fragment-based covalent ligand discovery

W. Lu, M. Kostic, T. Zhang, J. Che, M. P. Patricelli, L. H. Jones, E. T. Chouchani and N. S. Gray, RSC Chem. Biol., 2021, 2, 354
DOI: 10.1039/D0CB00222D

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