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

Publication date: Available online 19 January 2017
Source:Cell
Author(s): Christopher G. Parker, Andrea Galmozzi, Yujia Wang, Bruno E. Correia, Kenji Sasaki, Christopher M. Joslyn, Arthur S. Kim, Cullen L. Cavallaro, R. Michael Lawrence, Stephen R. Johnson, Iñigo Narvaiza, Enrique Saez, Benjamin F. 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.

Graphical abstract

Teaser

A chemical proteomics platform enables the global mapping of reversible small-molecule fragment-protein interactions in cells.


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