Targeted protein degradation using bivalent small molecules (such as PROTACs) is a new modality that provides a means to control protein levels <i>in vivo</i>. Despite many clear advantages, numerous challenges exist in the development of these molecules, particularly concerning the rational design of efficacious molecules. In this presentation, multiple computational methods that enable the <i>a priori </i>evaluation of putative degraders will be discussed. Numerous case studies will be presented, where the application of these computational tools can successfully recommend not only potent candidates, but also successfully suggest molecules to avoid. Results from scenarios across different target proteins, E3 ligases, and linker architectures will be presented. Finally, our latest innovations, such as KNIME integration and an extension into molecular glues, will be discussed.

Modeling targeted protein degradation via bifunctional degraders: Case studies and recent developments

ACS Spring 2022

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