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Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers.

  • Author(s): Sijbesma, Eline
  • Hallenbeck, Kenneth K
  • Andrei, Sebastian A
  • Rust, Reanne R
  • Adriaans, Joris MC
  • Brunsveld, Luc
  • Arkin, Michelle R
  • Ottmann, Christian
  • et al.

The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein-protein interactions (PPIs). We have previously shown that disulfide trapping successfully yielded covalent stabilizers for the PPI of 14-3-3 with the estrogen receptor ERα. Here we provide an assessment of the composite PPI target pocket and the molecular characteristics of various fragments binding to a specific subpocket. Evaluating structure-activity relationships highlights the basic principles for PPI stabilization by these covalent fragments that engage a relatively large and exposed binding pocket at the protein/peptide interface with a "molecular glue" mode of action.

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