Application of Weighted Interaction-Fingerprints for Rationalizing Neosubstrate Potency and Selectivity of...

Area of Science:

• Biochemistry
• Drug Discovery
• Structural Biology

Background:

• Cullin-RING Ligase 4 Cereblon (CRL4CRBN) E3 ligase modulatory drugs (CELMoDs) are a successful class of compounds.
• CELMoDs function by targeting neosubstrates for proteasome-dependent degradation.
• Current CELMoDs, including immunomodulatory drugs (IMiDs), target proteins like Ikaros and Aiolos, with ongoing trials for GSPT1, CK1α, and Helios.

Purpose of the Study:

• To develop a computational structure-based approach for analyzing and predicting ligand interactions in neosubstrate ternary complexes.
• To provide insights for designing more selective and efficacious Cereblon (CRBN)-based molecular glues.
• To optimize neosubstrate recruitment and degradation selectivity, minimizing potential off-target activity.

Main Methods:

• Utilized a computational structure-based approach.
• Analyzed and predicted putative ligand interactions within the neosubstrate ternary complex.
• Focused on understanding interactions mediated by non-canonical motifs beyond G-motifs.

Main Results:

• The computational approach provides valuable insights into ligand-neosubstrate interactions.
• Identified key interactions important for the ternary complex formation.
• Demonstrated the potential for enhanced design of CRBN-based molecular glues.

Conclusions:

• A computational structure-based method can effectively analyze and predict ligand interactions for CRBN-based molecular glues.
• This approach aids in the rational design of more selective and potent degradation-targeting therapeutics.
• Optimizing neosubstrate recruitment through understanding ternary complex interactions is crucial for minimizing off-target effects.