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Ligand and Target Discovery by Fragment-Based Screening in Human Cells.

Cell | Jan 26, 2017

Advances in the synthesis and screening of small-molecule libraries have accelerated the discovery of chemical probes for studying biological processes. Still, only a small fraction of the human proteome has chemical ligands. Here, we describe a platform that marries fragment-based ligand discovery with quantitative chemical proteomics to map thousands of reversible small molecule-protein interactions directly in human cells, many of which can be site-specifically determined. We show that fragment hits can be advanced to furnish selective ligands that affect the activity of proteins heretofore lacking chemical probes. We further combine fragment-based chemical proteomics with phenotypic screening to identify small molecules that promote adipocyte differentiation by engaging the poorly characterized membrane protein PGRMC2. Fragment-based screening in human cells thus provides an extensive proteome-wide map of protein ligandability and facilitates the coordinated discovery of bioactive small molecules and their molecular targets.

Pubmed ID: 28111073 RIS Download

Mesh terms: Adipocytes | Cell Differentiation | Crystallography, X-Ray | Drug Discovery | High-Throughput Screening Assays | Humans | Hydrolases | Ligands | Membrane Proteins | Oxidoreductases | Protein Binding | Proteomics | Receptors, Progesterone | Small Molecule Libraries

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