Covalent molecular fragment library for cysteine residues                               Competitive chemical proteomics platform for covalent ligand screening


Fragment-based ligand discovery (FBLD) has been widely used in the identification of drug lead compounds. This method is usually limited to a single protein system, which greatly limits its throughput. It is a good simulation of the interaction between protein and ligand in the natural state. The emergence of chemical proteomics technology has effectively solved this problem. It can directly screen lead compounds in complex biological systems (cell lysates or living cells), realize simultaneous analysis of multiple targets, and revolutionize FBLD. The era of high throughput. As shown in the figure above, the research group of Professor Cravatt of the Scripps Research Institute in the United States has constructed a library of covalent molecular fragments for cysteine residues. They have the same acrylamide or chloroacetamide as many covalent targeted drugs. Active reactive group. Using a competitive chemical proteomics platform, the probe labeling intensity of each active cysteine residue is quantitatively read, and this data is directly related to the labeling intensity of the protein by the covalent molecular ligand. Therefore, chemical proteomics technology based on mass spectrometry accelerates the screening of lead compounds for covalent drugs, helps us realize large-scale exploration of potential ligand binding pockets at the level of complex proteomics, and provides opportunities for targeting "undruggable" proteins. . (Proteome-wide covalent ligand discovery in native biological systems. Nature. 2016, 534, 570-4.)