Targeted Protein Degradation with Discovery Studio
Novel strategies for designing therapies do not appear often, and targeted protein degradation, TPD, is one of such fairly recent novel strategies.
Our customer C4 Therapeutics is actively developing this technique.
The company says:
Targeted protein degradation harnesses the cell’s innate capability to control protein levels to remove known drivers of disease.
TPD method marks a protein for destruction, most often by using a so-called degrader molecule. The process is based on generation of an intermediary ternary complex – target–degrader–ligase.
Target–degrader–ligase leads to a destruction of protein through a natural cellular process called ubiquitination. Degraders differ from inhibitors – they actually destroy target proteins rather than limiting their activity.
A recent paper by C4 Therapeutics with BIOVIA’s Jodi Shaulsky combines experimental and computational tools to offer a workflow to provide rapidly accessible structural insights into degrader-induced protein–protein interfaces in solution.
The paper Structural Characterization of Degrader-Induced Ternary Complexes Using Hydrogen–Deuterium Exchange Mass Spectrometry and Computational Modeling: Implications for Structure-Based Design appeared in the ACS Chemical Biology journal.
Discovery Studio’s CHARMm was used to package protein-degrader complexes, and they were scored for complementarity using the protein-protein binding ZRANK scoring. This work creates an interesting template for TPD studies, using e.g. PROTAC® methodology.