Fr-PPIChem: An Academic Compound Library Dedicated to Protein-Protein Interactions.

Area of Science:

• Drug discovery and medicinal chemistry
• Molecular biology and cell signaling
• Computational chemistry and cheminformatics

Background:

• Protein-protein interactions (PPIs) are crucial for cellular functions and disease, but challenging drug targets.
• Existing screening libraries yield low hit rates for PPI inhibitors (iPPIs) due to unsuitable compound collections.
• Developing effective small molecule iPPIs requires innovative screening approaches and targeted chemical libraries.

Purpose of the Study:

• To construct a novel, curated chemical library specifically designed for the high-throughput screening of PPI inhibitors.
• To leverage predictive modeling and medicinal chemistry principles to enrich the library with drug-like PPI-targeting compounds.
• To enhance the discovery of chemical probes and early drug leads for therapeutic intervention in diseases mediated by PPIs.

Main Methods:

• Development of predictive models using machine learning and databases of known PPI inhibitors.
• Selection of compounds from commercial collections based on complementarity and predictive model scores.
• Application of medicinal chemistry filters (e.g., PAINS, toxicity) and clustering for library optimization.
• Validation of the library's efficacy using high-throughput screening against the CD47-SIRPα PPI.

Main Results:

• The Fr-PPIChem library demonstrated a 46-fold increase in activity rate compared to a standard diversity library in screening against the CD47-SIRPα PPI.
• Predictive models and medicinal chemistry filters successfully enriched the library with putative PPI inhibitors.
• The library's chemical diversity was maintained while reducing its size through clustering.

Conclusions:

• The Fr-PPIChem library represents a powerful, optimized resource for accelerating the discovery of PPI inhibitors.
• This curated library significantly improves the efficiency of high-throughput screening for identifying novel chemical probes and drug candidates.
• The Fr-PPIChem library is available to the scientific community, facilitating research in PPI-targeted drug development.