Ligand and target discovery by fragment-based screening in human cells

• Christopher G. Parker ^[1] ; Andrea Galmozzi ^[1] ; Yujia Wang ^[1]
  1. [1] Scripps Research Institute

     Scripps Research Institute

     Estados Unidos

     
• Localización: Cell, ISSN 0092-8674, Vol. 168, Nº. 3, 2017, págs. 527-541
• Idioma: inglés
• Texto completo no disponible (Saber más ...)
• Resumen

  • 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.