Speaker:

Koushik Kasavajhala, Senior Scientist II, Schrödinger

Abstract:

Proteolysis-targeting chimeras (PROTACs) are an emerging area of drug discovery. Unlike traditional small-molecule inhibitors that block protein activity, PROTACs modulate protein function by inducing protein degradation. They bring the target protein and an E3 ubiquitin ligase into proximity, leading to the target protein’s ubiquitination and subsequent degradation by the proteasome. Designing a PROTAC involves optimization of the individual binding domains (also known as warheads) that bind to the target protein and the ligase, the linker connecting the two warheads, and the formation of a ternary complex (target protein + ligase + PROTAC). In this webinar, we will present Schrodinger’s advanced computational toolkit to generate and score potential ternary complexes, and to optimize warheads and linkers. The toolkit uses a combination of protein-protein docking, linker sampling, enhanced sampling methods, and free energy perturbation (FEP+) calculations to design PROTACs with improved degrader potency.