Despite continued development of new ligand discovery methods, it remains challenging to identify hits for a significant palette of targets e.g. protein-protein interaction (PPI) inhibitors/stabilizers. Fragment-based-drug-discovery (FBDD) has proven powerful in furnishing starting points for PPI inhibitor candidates and led to development of clinically approved drugs. However, identification of fragments that can serve as starting points for the elaboration of PPI stabilizers presents specific challenges given the need to form a termolecular complex paired with typically weak fragment binding. Disulfide tethering has proven useful in developing PPI inhibitors, allosteric modulators, and tools to study aggregation. Recently the method was shown to be useful for site-directed fragment identification using the 14-3-3σ/ERα interface as a model. 40-fold stabilization was achieved for binding of a C-terminal ERα peptide by 14-3-3 in the presence of the protein-fragment adduct, although stabilization in the absence of the disulfide tether remains to be reported.