Parker, C.G. et al. Cell 168, 527–541.e29 (2017).

Much of the human proteome is considered 'undruggable'—that is, it has been difficult to identify ligands to inhibit most of its proteins. New inhibitors can be found by phenotype-based screening of libraries of small molecules in cells, but the major challenge is pinpointing a ligand's target(s). Parker et al. describe the combination of fragment-based screening with quantitative chemical proteomics. They use low-molecular-weight simple compounds, referred to as fragments, to find low-affinity interactions; the fragment hits serve as starting points for developing more potent inhibitors. To identify fragment targets with certainty, they created a reagent consisting of the fragment, photoreactive crosslinker, and a chemical handle for screening and capturing target proteins, which can then be identified by mass spectrometry. In applying their method, the authors identified ligands for the protein PGRMC2, which promotes adipocyte differentiation.