Characterising Covalent Warhead Reactivity

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

Research output: Contribution to journalArticle

1 Citation (Scopus)
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Abstract

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
Volume27
Issue number10
Early online date3 Apr 2019
DOIs
Publication statusPublished - 15 May 2019

Fingerprint

Toxicity
Pharmaceutical Preparations
Aptitude
Pharmacokinetics
Threonine
Histidine
Serine
Lysine
Fear
Cysteine
Tyrosine
Arginine
Assays
Catalytic Domain
Nuclear magnetic resonance
Amino Acids
Proteins
Inhibition (Psychology)

Keywords

  • Covalent drug
  • Reactivity
  • Warhead

Cite this

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abstract = "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.",
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