Ligand and Target Discovery by Fragment-Based Screening in Human Cells.
Cell
; 168(3): 527-541.e29, 2017 01 26.
Article
in En
| MEDLINE
| ID: mdl-28111073
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Proteomics
/
Drug Discovery
Type of study:
Diagnostic_studies
/
Screening_studies
Limits:
Humans
Language:
En
Journal:
Cell
Year:
2017
Document type:
Article