Recently, bifunctional small molecules known as Proteolysis-Targeting Chimeras, or PROTACs, have been the focus of intense research. PROTACs have the potential to offer a new modality in drug discovery, as a PROTAC tags a targeted protein for degradation rather than inhibition. Despite the demonstration of numerous advantages, the eventual success of the PROTAC approach hinges upon, among other factors, the ability to rationally modify and eventually design new PROTAC molecules. We have developed a suite of tools for predicting the structures of ternary complexes, which are at the heart of successful protein degradation. In addition to generating a large ensemble of possible structures, we propose metrics that have been developed based on available experimental knowledge to identify the structures that are likely to degrade. We demonstrate the utility of our methods in a number of scenarios, including across different targets and PROTAC molecules.

Predicting protein degradation through computational modeling of PROTAC-mediated ternary complexes

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.