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Keywords:

  • fragments;
  • ligand design;
  • mass spectrometry;
  • Michael additions;
  • protein modifications
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Birds of a tether: A tethering strategy for the site-directed discovery of low-molecular-weight fragments that bind weakly to defined protein surfaces is described. A solvent-exposed protein thiol captures acrylamide-modified fragments in a conjugate addition reaction that requires a template to produce a measureable quantity of protein–fragment adduct, which can be rapidly identified by mass spectrometry.