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

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

  • Cell. 2017 Jan 26;168(3):527-541.e29. doi: 10.1016/j.cell.2016.12.029.
Christopher G Parker 1,  Andrea Galmozzi 2,  Yujia Wang 2,  Bruno E Correia 3,  Kenji Sasaki 2,  Christopher M Joslyn 2,  Arthur S Kim 2,  Cullen L Cavallaro 4,  R Michael Lawrence 4,  Stephen R Johnson 4,  Iñigo Narvaiza 5,  Enrique Saez 6,  Benjamin F Cravatt 7
Affiliations

Affiliations

  • 1 Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: cparker@scripps.edu.
  • 2 Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 3 École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
  • 4 Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08648, USA.
  • 5 The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
  • 6 Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: esaez@scripps.edu.
  • 7 Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: cravatt@scripps.edu.
PMID: 28111073 DOI: 10.1016/j.cell.2016.12.029
Abstract

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.

Keywords

FBLD; PGRMC2; adipogenesis; chemical probes; chemical proteomics; fragment-based ligand discovery; ligands; mass spectrometry; phenotypic screening; photoreactivity.

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