Query-guided protein-protein interaction inhibitor discovery.

Area of Science:

• Drug Discovery
• Structural Biology
• Computational Chemistry

Background:

• Protein-protein interactions (PPIs) are crucial for biological processes and represent important drug targets.
• Developing small molecule inhibitors for PPIs is challenging due to large, shallow interaction surfaces.

Purpose of the Study:

• To develop a general strategy for discovering orthosteric inhibitors of PPIs by mimicking protein secondary structures.
• To validate the approach using experimentally relevant PPIs mediated by alpha-helices and beta-strands.

Main Methods:

• Identification of key 'hot residues' at protein interfaces.
• Generation of secondary structure-based queries for virtual screening.
• Shape matching of small molecules against queries and subsequent docking.
• Experimental validation using fluorescence anisotropy and HSQC experiments.

Main Results:

• Discovery of selective PPI inhibitors with low micromolar activity for both p53/hDM2 (alpha-helix mediated) and GKAP/SHANK1-PDZ (beta-strand mediated) interactions.
• Successful hit expansion leading to inhibitors with established structure-activity relationships.

Conclusions:

• The described general approach is effective for discovering inhibitors of secondary structure-mediated PPIs.
• This strategy holds potential for broad application in targeting diverse PPIs for therapeutic intervention.