A panel of three proteins was selected for screening SF reactive fragment libraries: CAII, KRAS4B G12D , and BCL6. These proteins were selected to sample broad structural diversity and biological function, while also being of therapeutic relevance. None of the proteins contain a catalytic nucleophilic amino acid residue, which allowed us to probe the utility of the SFs in targeting nucleophilic amino acid residues present in the vicinity of binding pockets.