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

Area of Science:

• Chemical Biology
• Proteomics
• Drug Discovery

Background:

• Limited availability of chemical ligands for the human proteome hinders biological process studies.
• Existing methods for discovering chemical probes are insufficient for proteome-wide coverage.

Purpose of the Study:

• To develop a platform for mapping small molecule-protein interactions directly in human cells.
• To identify novel chemical probes and bioactive small molecules targeting previously uncharacterized proteins.

Main Methods:

• Integration of fragment-based ligand discovery with quantitative chemical proteomics.
• Direct mapping of reversible small molecule-protein interactions within human cells.
• Advancement of fragment hits to selective ligands and combination with phenotypic screening.

Main Results:

• Thousands of reversible small molecule-protein interactions were mapped, many site-specifically.
• Development of selective ligands for proteins lacking prior chemical probes.
• Identification of small molecules promoting adipocyte differentiation via engagement of PGRMC2.

Conclusions:

• The developed platform provides a proteome-wide map of protein ligandability in human cells.
• Facilitates simultaneous discovery of bioactive small molecules and their protein targets.
• Enables the study of proteins, like PGRMC2, that were previously difficult to probe.