On Ternary Complex Stability in Protein Degradation: In Silico Molecular Glue Binding Affinity Calculations

Area of Science:

• Chemical Biology
• Structural Biology
• Drug Design

Background:

• Molecular glues are small molecules that induce protein-protein interactions.
• Cereblon E3 ligase modulators (CELMoDs) are a class of molecular glues that recruit neosubstrates to the cereblon (CRBN) E3 ubiquitin ligase for degradation.
• Ternary complex structures of clinical CELMoDs (CC-885, CC-90009) bound to CRBN and neosubstrates (GSPT1) have been determined.

Purpose of the Study:

• To assess the utility of structure-based drug design principles in predicting CELMoD binding affinity.
• To correlate predicted binding affinity with measured cellular degradation potency for neosubstrates.
• To evaluate CELMoD efficacy for neosubstrates GSPT1 and zinc finger Aiolos (IKZF3).

Main Methods:

• Utilized established structure-based methods to analyze in silico ternary complex stabilities.
• Tested a congeneric series of CELMoDs with similar binding events and modes.
• Correlated predicted binding affinities with experimentally measured cellular degradation potencies.

Main Results:

• Structure-based methods successfully predicted the relative binding affinities of CELMoDs within the ternary complex.
• A strong correlation was observed between predicted binding affinity and measured cellular degradation potency.
• The findings were consistent for neosubstrates GSPT1 and IKZF3.

Conclusions:

• Well-established structure-based methods are applicable for predicting CELMoD binding affinity to the induced protein-protein neointerface.
• In silico ternary complex stability measurements can accurately predict the relative degradation potency of CELMoDs.
• This approach aids in the rational design and optimization of CELMoD-based therapeutics.