The reactivity of amino acid residues in proteins plays a crucial role in protein function regulation and drug development. Taking cysteine as an example, although it constitutes only 1.4% of the proteome, its distribution is relatively uniform. Due to its highly chemically reactive thiol group, it is primarily found in disulfide bonds, enzyme active sites, metal ligand binding sites, and small molecule drug binding pockets. As a result, many covalent drugs target cysteine residues, such as small molecule kinase covalent drugs (link). Most antibody-drug conjugates (ADC) also use cysteine residues to conjugate small molecule drugs to the antibody surface. There are various post-translational modifications on cysteine residues, such as S-nitrosylation, sulfinylation, and thioesterification, which regulate protein structure and interactions. In addition, lysine, serine, methionine, tyrosine, and histidine residues in proteins also exhibit unique chemical reactivity, making them applicable in the development of covalent drugs and selective protein labeling.

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