Screening-based approaches to identify small molecules that inhibit protein-protein interactions

Area of Science:

• Drug discovery and development
• Molecular biology
• Pharmacology

Background:

• Protein-protein interactions (PPIs) are crucial in disease regulation and represent attractive drug targets.
• The functionally critical regions of most PPIs are amenable to modulation by small molecules.
• Significant advancements have been made in identifying PPI inhibitors, driven by innovative screening technologies.

Purpose of the Study:

• To review current screening technologies for identifying small molecule inhibitors of PPIs.
• To evaluate the suitability of PPIs as molecular targets for therapeutic intervention.
• To outline compound selection processes, including binding affinity, kinetics, structural, and cellular assays.

Main Methods:

• Literature review of screening technologies for PPI inhibitors.
• Analysis of methodologies for assessing compound binding affinity and kinetics.
• Discussion of structural analysis and cellular function assays for PPI inhibitors.

Main Results:

• Various screening technologies enable the identification of small molecule PPI inhibitors.
• A multi-step process involving binding, kinetic, structural, and cellular assays is crucial for candidate assessment.
• Despite challenges, PPI inhibitors show potential as first-in-class therapeutics.

Conclusions:

• Targeting PPIs remains challenging, with few candidates in clinical development.
• Comprehensive assessment using multiple assay systems is vital for optimizing small molecule PPI inhibitors.
• Small molecule PPI inhibitors offer a promising therapeutic avenue for various diseases.