Modeling Targeted Protein Degradation via Bifunctional Degraders and Molecular Glues
In recent years, targeted protein degradation has emerged as a new modality to control protein levels in vivo. Both heterobifunctional and molecular glues can be developed to selectively and catalytically target a protein-of-interest for degradation. Despite the many advantages of these approaches, numerous challenges still exist in the development of degraders, particularly concerning the rational design of efficacious molecules. This talk will explore the most promising methodologies we have developed to evaluate putative degrader designs. Recent case studies will be presented, demonstrating in particular the utility of these approaches on larger-scale degrader investigations. Particular focus will be given to the quality of the predictions as a function of available input knowledge, such as using hydrogen-deuterium exchange (HDX) data to inform protein-protein interface prediction and, ultimately, ternary complex geometry.
