Proteome-Wide Fragment-Based Ligand and Target Discovery

Area of Science:

• Chemical biology
• Proteomics
• Drug discovery

Background:

• Chemical probes are essential for biological research and therapeutic development.
• Limited availability of selective chemical probes hinders the exploration of many potential drug targets.
• The "chemically-tractable" proteome remains largely uncharacterized, representing a significant gap in knowledge.

Purpose of the Study:

• To review advanced chemical proteomic approaches for surveying protein ligandability.
• To highlight the integration of chemoproteomics with fragment-based ligand discovery (FBLD).
• To facilitate the mapping of the ligandable proteome and identify starting points for chemical probe development.

Main Methods:

• Global surveying of protein-small molecule binding (ligandability) in native systems.
• Application of chemical proteomic techniques.
• Integration with fragment-based ligand discovery (FBLD) methodologies.

Main Results:

• Development of powerful chemical proteomic approaches enables global ligandability surveys.
• Integration with FBLD provides a strategy for broad proteome mapping.
• These methods offer starting points for developing novel chemical probes.

Conclusions:

• Chemical proteomic strategies are vital for expanding the repertoire of chemical probes.
• Mapping the ligandable proteome is key to unlocking new therapeutic targets.
• The combined use of chemoproteomics and FBLD accelerates the discovery of lead chemical probes.