CMSA Interdisciplinary Science Seminar: In silico design and evaluation of PROTAC-based protein degrader–Introductory case studies
Shang Su - Department of Cancer Biology, The University of Toledo
Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules consisting of two chemical moieties connected by a linker. The simultaneous binding of a PROTAC to both a target protein and an E3 ligase facilitates ubiquitination and degradation of the target protein. Since its proof-of-concept research in 2001, PROTAC has been vigorously developed by both research community and pharma industry, to act against therapeutically significant proteins, such as BRD4, BTK, and STAT3. However, despite the enthusiasm, designing PROTACs is challenging. Till now, no case of de novo rational design of PROTACs has been reported and the successful PROTACs usually came from the functional screen from a limitedly scaled library. As formation of a ternary complex between the protein target, the PROTAC, and the recruited E3 ligase is considered paramount for successful degradation, several computational algorithms (PRosettaC as the example), have been developed to model this ternary complex, which have got partial agreement with the experimental data and in principle inform future rational PROTAC design. Here I will introduce some of these computational methods and share how they model the ternary complexes.