Protein-ligand interactions have been utilized for a variety of catalytic transformation by enhancing inherently slow reactions through proximity-driven effects (Scheme 16B). Early examples of ligand-directed labeling strategies (non-catalytic) were shown to modify active sites of enzymes and antibody binding sites. Such early examples were not catalytic, as the bound ligand does not dissociate after the labeling process. More recently, catalytic ligand-directed strategies have been reported where types of ligands range from small molecules to peptide ligands, and various catalysis, as described in the previous sections (i.e., photocatalysis, transition-metal catalysis, and organocatalysis). The proximity effect is often utilized for sluggish reactions that do not proceed without the rate enhancement mechanism, including examples of ruthenium photocatalysis and DMAP-based organocatalysis. In other words, generally unreactive amino acid residues could be modified through the proximity effects, as modification of phenylalanine was achieved by dirhodium catalyst conjugated with STAT3 ligand. The proximity-driven rhodium catalysis was indeed shown to be capable of modification of half of canonical amino acids, including asparagine, phenylalanine, glutamine, and threonine, showcasing the power of the supramolecular chemistry. Scheme 16. Supramolecular catalysis. (A) Schematic illustration and mechanism of the protein modification with supramolecular catalysts. (B) Structure of supramolecular catalysts and catalysis mechanisms. Top: Reductive amination catalyzed through the supramolecular interaction between the gallium cluster, pyridine-borane, and imine intermediate. Middle: Thia-Michael addition to a cysteine residue facilitated by the interaction between a tryptophan residue of a protein and bipyridinium unit of the labeling reagent in the cucurbit [8]uril (CB [8]) as a supramolecular host. The image of X-ray crystal structure on the right was reproduced with permission. Copyright 2000, American Chemical Society. Bottom: Proximity-driven catalysis through binding of a ligand to target proteins.