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Characterising covalent warhead reactivity.

James S Martin1, Claire J MacKenzie1, Daniel Fletcher1

  • 1Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.

Bioorganic & Medicinal Chemistry
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Understanding covalent inhibitor reactivity is key for drug development. This study measured warhead reactivity against various amino acids to guide the design of safer, targeted covalent drugs.

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Covalent drugReactivityWarhead

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Area of Science:

  • Medicinal Chemistry
  • Drug Discovery
  • Chemical Biology

Background:

  • Covalent inhibitors offer pharmacokinetic advantages but carry toxicity risks due to potential off-target binding.
  • Historically, covalent drug discovery relied on serendipity, with organizations hesitant due to safety concerns.
  • Renewed interest in covalent modifiers is driven by the potential for highly selective compounds.

Purpose of the Study:

  • To quantify the reactivity of various covalent warheads against common and non-traditional amino acid residues.
  • To assess the impact of environmental factors, such as pH, on covalent inhibitor reactivity.
  • To provide data for selecting appropriately reactive warheads to minimize toxicity and maximize target specificity.

Main Methods:

  • Development and application of a robust Nuclear Magnetic Resonance (NMR) based assay.
  • Measurement of covalent warhead reactivity against serine, cysteine, threonine, tyrosine, lysine, histidine, and arginine.
  • Reactivity assessments conducted across a range of pH values to simulate physiological conditions.

Main Results:

  • Covalent warhead reactivity is significantly influenced by the specific amino acid residue.
  • The assay successfully quantified reactivity, enabling comparative analysis of different warheads.
  • Reactivity varied considerably across tested amino acids and under different pH conditions.

Conclusions:

  • Warhead reactivity is highly dependent on the target amino acid residue, a critical factor in covalent drug design.
  • This research provides essential data for the rational design of selective covalent inhibitors.
  • Understanding residue-specific reactivity is crucial for mitigating toxicity and advancing covalent drug discovery.