Characterising Covalent Warhead Reactivity

James Martin, Claire Mackenzie, Daniel Fletcher, Ian Gilbert (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

72 Citations (Scopus)
414 Downloads (Pure)


Many drugs currently used are covalent inhibitors and irreversibly inhibit their targets. Most of these were discovered through serendipity. Covalent inhibitions can have many advantages from a pharmacokinetic perspective. However, until recently most organisations have shied away from covalent compound design due to fears of non-specific inhibition of off-target proteins leading to toxicity risks. However, there has been a renewed interest in covalent modifiers as potential drugs, as it possible to get highly selective compounds. It is therefore important to know how reactive a warhead is and to be able to select the least reactive warhead possible to avoid toxicity. A robust NMR based assay was developed and used to measure the reactivity of a variety of covalent warheads against serine and cysteine – the two most common targets for covalent drugs. A selection of these warheads also had their reactivity measured against threonine, tyrosine, lysine, histidine and arginine to better understand our ability to target non-traditional residues. The reactivity was also measured at various pHs to assess what effect the environment in the active site would have on these reactions. The reactivity of a covalent modifier was found to be very dependent on the amino acid residue.

Original languageEnglish
Pages (from-to)2066-2074
Number of pages9
JournalBioorganic & Medicinal Chemistry
Issue number10
Early online date3 Apr 2019
Publication statusPublished - 15 May 2019


  • Covalent drug
  • Reactivity
  • Warhead

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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