The Applications of Computational Tools in PROTAC Development

Abstract: The increasing importance of PROTACs (proteolysis-targeting chimeras) has attracted significant attention from both the academic community and industry. PROTACs are heterobifunctional small molecules that can bind to both the protein of interest (POI) and the E3 ubiquitin ligase (E3), inducing ubiquitinated degradation of POI. The unique mechanisms of PROTACs, such as event-driven pharmacology and modulation of protein degradation, provide novel therapeutic modalities for various diseases, including oncology, antiviral therapies, neurodegenerative diseases, acne, and others. Numerous computational methods, including structural prediction, molecular generation, and molecular dynamics simulation, have been applied in the development of PROTAC molecules. This review introduces the fundamental principles of computational tools used in PROTAC design, as well as typical examples validated by experiments.