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The ionization of a molecule into a molecular ion inside the mass spectrometer causes instability in the molecule's structure due to the loss of an electron. This eventually leads to the fragmentation or breaking of some bonds in the molecule. The fragmentation occurs predominantly at specific bonds to yield relatively stable fragments.
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The molecular orbital theory describes the distribution of electrons in molecules in a manner similar to the distribution of electrons in atomic orbitals. The region of space in which a valence electron in a molecule is likely to be found is called a molecular orbital. Mathematically, the linear combination of atomic orbitals (LCAO) generates molecular orbitals. Combinations of in-phase atomic orbital wave functions result in regions with a high probability of electron density, while...
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Bond energy is the energy required to break a bond homolytically. These values are usually expressed in units of kcal/mol or kJ/mol and are referred to as bond dissociation energies when given for specific bonds or average bond energies when indicated for a given type of bond over many compounds. Firstly, the bond dissociation energy for a single bond is weaker than that of a double bond, which in turn is weaker than that of a triple bond. Secondly, hydrogen forms relatively strong bonds with...
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Updated: Dec 15, 2025

Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay
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Multiparameter Kinetic Analysis for Covalent Fragment Optimization by Using Quantitative Irreversible Tethering

Gregory B Craven1,2, Dominic P Affron2, Teresa Kösel2

  • 1Department of Life Sciences, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.

Chembiochem : a European Journal of Chemical Biology
|July 14, 2020
PubMed
Summary

We developed a new method for discovering covalent chemical probes by analyzing binding kinetics. This data-driven approach optimizes probe potency and selectivity for targeted biological investigations.

Keywords:
Cdk2covalent fragmentscovalent inhibition kineticselectrophile-sensitive inhibitionfragment-based drug discovery

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Area of Science:

  • Chemical Biology
  • Biochemistry
  • Drug Discovery

Background:

  • Covalent chemical probes targeting cysteine residues are vital for biological research.
  • Optimizing covalent fragments for probes is challenging due to complex structure-activity relationships.

Purpose of the Study:

  • To introduce a novel platform for data-driven optimization of covalent fragment probes.
  • To enable rapid multiparameter kinetic analysis for improved probe discovery.

Main Methods:

  • Developed a technique for simultaneous determination of Ki, kinact, and intrinsic reactivity.
  • Applied the platform to identify covalent probes against electrophile-sensitive kinases.

Main Results:

  • Successfully optimized covalent fragment potency and selectivity.
  • Demonstrated utility in hit identification for kinase targets.
  • Enabled a fragment-merging strategy through multiparameter kinetic analysis.

Conclusions:

  • The new platform facilitates efficient covalent probe discovery.
  • Multiparameter kinetic analysis is key for optimizing covalent fragment-based probes.
  • This approach advances the development of targeted chemical tools for biological studies.