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Related Concept Videos

Ligand Binding Sites02:40

Ligand Binding Sites

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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
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Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
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Ligand discovery by activity-based protein profiling.

Micah J Niphakis1, Benjamin F Cravatt2

  • 1Lundbeck La Jolla Research Center Inc., San Diego, CA, USA.

Cell Chemical Biology
|September 20, 2024
PubMed
Summary
This summary is machine-generated.

Activity-based protein profiling (ABPP) maps small molecule interactions to guide chemical probe and drug discovery for challenging proteins. This approach addresses the "druggability" of the human proteome by revealing novel therapeutic mechanisms.

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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.