A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins

Area of Science:

• Drug discovery and development
• Structural biology
• Chemical biology

Background:

• Target class-focused drug discovery is effective, but many protein families, like WD40 repeat (WDR) proteins, lack known small molecule ligands.
• The WDR protein family is highly relevant in disease but remains underexplored for therapeutic targeting.

Purpose of the Study:

• To develop a systematic and scalable approach for discovering and characterizing small molecule ligands for the WDR protein family.
• To evaluate the broader ligandability of WDR proteins and establish a template for family-wide assessment.

Main Methods:

• Developed comprehensive protocols for protein production, crystallography, and various biophysical, biochemical, and cellular assays.
• Employed DNA-encoded chemical library selection combined with machine learning (DEL-ML) for hit identification.
• Screened virtual libraries to predict potential ligands.

Main Results:

• Successfully identified first-in-class, drug-like small molecule ligands for 7 out of 16 screened WDR domains.
• Demonstrated the significant ligandability of the WDR protein family.
• Generated a comprehensive resource of biochemical and chemical tools, knowledge, and protocols for WDR proteins.

Conclusions:

• The developed systematic approach provides a scalable template for evaluating protein family-wide ligandability.
• The findings highlight the therapeutic potential of targeting the WDR protein family, previously considered underexplored.
• This study provides valuable tools and knowledge to accelerate the discovery of potential therapeutics for WDR-related diseases.