Ligand and Target Discovery by Fragment-Based Screening in Human Cells.
Research paper by
Christopher G CG Parker, Andrea A Galmozzi, Yujia Y Wang, Bruno E BE Correia, Kenji K Sasaki, Christopher M CM Joslyn, Arthur S AS Kim, Cullen L CL Cavallaro, R Michael RM Lawrence, Stephen R SR Johnson, Iñigo I Narvaiza, Enrique E Saez, Benjamin F BF Cravatt
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.