Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation via New In...

Area of Science:

• Computational chemistry
• Structural biology
• Drug discovery

Background:

• Proteolysis Targeting Chimeras (PROTACs) offer a novel therapeutic strategy by inducing targeted protein degradation.
• Accurate modeling of PROTAC-mediated ternary complexes is crucial for predicting degradation efficacy.
• Previous computational approaches have limitations in modeling these complex structures.

Purpose of the Study:

• To present and validate two novel computational methods for modeling PROTAC-mediated ternary complex structures.
• To assess the ability of these methods to predict protein degradation efficacy.
• To facilitate PROTAC screening and design efforts.

Main Methods:

• Development and application of Method 4B, incorporating a clustering procedure for ternary complex modeling.
• Validation against known crystal structures of ternary complexes.
• Retrospective case studies involving seven different PROTAC-mediated degradation scenarios.

Main Results:

• Method 4B achieves a high proportion of crystal-like poses in modeled ternary complex ensembles, with hit rates of at least 10%.
• The methods successfully reproduce newly released crystal structures and demonstrate reliability in predicting degradation trends for unknown ternary complex structures.
• Effective modeling was achieved across diverse scenarios, including various PROTACs, target proteins, and uncharacterized E3 ligases.

Conclusions:

• The presented computational modeling approaches significantly enhance the ability to predict PROTAC efficacy.
• These methods can reliably model ternary complex structures, even in challenging and experimentally uncharacterized situations.
• The developed tools are expected to accelerate and reduce the cost of PROTAC screening and design.