Ligand discovery by activity-based protein profiling

Area of Science:

• Chemical biology
• Genomics
• Drug discovery

Background:

• Genomic technologies have advanced understanding of human gene function and disease relevance.
• Chemical biologists leverage this information for prioritizing proteins in drug development.
• Protein diversity poses challenges for conventional drug screening and assay development, questioning proteome "druggability".

Purpose of the Study:

• To propose activity-based protein profiling (ABPP) as a key technology for overcoming obstacles in chemical probe and drug discovery.
• To highlight ABPP's capability in generating comprehensive maps of small molecule-protein interactions within native biological systems.
• To demonstrate ABPP's utility in guiding the development of chemical probes and drugs against diverse and historically undruggable proteins.

Main Methods:

• Activity-based protein profiling (ABPP) to map global small molecule-protein interactions.
• Utilizing case studies to illustrate ABPP's application in chemical biology.
• Investigating small molecule mechanisms including disruption/stabilization of biomolecular interactions.

Main Results:

• ABPP generates global interaction maps, aiding in the prioritization of drug targets.
• Case studies demonstrate ABPP's ability to illuminate diverse small molecule mechanisms.
• Allostery is identified as a promising avenue for targeting previously undruggable proteins.

Conclusions:

• ABPP is a powerful approach to address challenges in human biology-guided chemical probe and drug discovery.
• ABPP facilitates the development of chemical tools for historically undruggable protein classes.
• The study underscores the potential of ABPP in expanding the scope of druggable targets within the human proteome.