Ligand and Target Discovery by Fragment-Based Screening in Human Cells
| Autor: | Enrique Saez, Kenji Sasaki, Christopher G. Parker, Benjamin F. Cravatt, Arthur S. Kim, Christopher M. Joslyn, Iñigo Narvaiza, Stephen R. Johnson, Cullen L. Cavallaro, Bruno E. Correia, R. Michael Lawrence, Andrea Galmozzi, Yujia Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Proteomics Hydrolases Phenotypic screening Computational biology Biology Crystallography X-Ray Ligands 01 natural sciences General Biochemistry Genetics and Molecular Biology Article Small Molecule Libraries 03 medical and health sciences High-Throughput Screening Assays Drug Discovery Human proteome project Adipocytes Humans Chemoproteomics 010405 organic chemistry Drug discovery Membrane Proteins Cell Differentiation Small molecule Molecular biology 0104 chemical sciences 030104 developmental biology Oxidoreductases Receptors Progesterone Protein Binding |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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