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Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
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Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
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Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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Mapping the SHP2 Allosteric Pocket With Target-Biased Covalent Fragments.

Nina-Louisa Efrém1,2, Noémi Csorba3,4,5, Machoud Amoussa1,6

  • 1Medicinal Chemistry, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.

Chembiochem : a European Journal of Chemical Biology
|April 25, 2026
PubMed
Summary
This summary is machine-generated.

Targeted covalent inhibitors (TCIs) can be developed by enhancing fragments with noncovalent interactions. This approach successfully identified a reactive site on the SHP2 phosphatase for new TCI drug development.

Keywords:
SHP2SuFExallosteric inhibitioncovalent fragmentsphosphatases

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Area of Science:

  • Medicinal Chemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • Targeted covalent inhibitors (TCIs) offer high selectivity and sustained effects by forming covalent bonds with target proteins.
  • Identifying suitable electrophilic warheads and nucleophilic amino acids is a key challenge in TCI development.
  • Conventional covalent fragment libraries may not effectively probe functionally relevant binding sites due to weak interactions.

Purpose of the Study:

  • To covalently map the tunnel allosteric site of the oncogenic phosphatase SHP2.
  • To explore the combination of covalent fragment screening with inhibitor pharmacophores.
  • To identify optimal warheads and reactive amino acids for SHP2 TCI development.

Main Methods:

  • Utilized aryl sulfonyl fluoride (SF) fragments incorporating pharmacophore elements (target-biased fragments).
  • Employed covalent fragment screening combined with established inhibitor pharmacophores.
  • Assessed covalent targeting of lysine 492 (K492) in the SHP2 tunnel binding site.

Main Results:

  • Target-biased SF fragments covalently targeted K492 in the SHP2 tunnel site.
  • Conventional SF fragments without enhanced noncovalent features did not react with K492.
  • Covalent engagement of K492 enhanced SHP2 enzyme inhibition.

Conclusions:

  • Noncovalent interactions are crucial in directing covalent fragment binding.
  • Target-biased fragments are a valuable strategy for identifying reactive sites and warheads in relevant binding pockets.
  • This study provides a foundation for developing novel SHP2 TCIs.