Quantifying Cooperativity through Binding Free Energies in Molecular Glue Degraders

Area of Science:

• Biochemistry
• Computational Chemistry
• Drug Discovery

Background:

• Molecular glues are a novel therapeutic strategy that stabilizes protein-protein interactions (PPIs).
• This enables targeting of proteins previously considered undruggable.
• Understanding cooperative binding is key to designing effective molecular glues.

Purpose of the Study:

• To develop and validate a computational protocol for screening molecular glues.
• To accurately assess the cooperative binding of ligands in ternary complexes.
• To identify potent molecular glue degraders for targeted protein degradation.

Main Methods:

• Pathway-independent free energy calculation to assess cooperativity.
• Combined ligand and protein free energy perturbation (FEP) for ternary binding analysis.
• High-throughput virtual screening of large molecular libraries.

Main Results:

• The computational protocol accurately predicts ligand-induced PPIs and degradation potential.
• Benchmarking against experimental data for cereblon (CRBN)-Ikaros complexes confirmed high accuracy.
• L4 and L5 were identified as top-performing molecular glues, with novel candidates discovered via screening.

Conclusions:

• The developed computational protocol is effective for identifying potent molecular glues.
• This approach advances targeted protein degradation strategies.
• The findings pave the way for broader applications of molecular glues in drug discovery.