PROflow: An iterative refinement model for PROTAC-induced structure prediction

Proteolysis targeting chimeras (PROTACs) are small molecules that trigger the breakdown of traditionally "undruggable" proteins by binding simultaneously to their targets and degradation-associated proteins. A key challenge in their rational design is understanding their structural basis of activity. Due to the lack of crystal structures (18 in the PDB), existing PROTAC docking methods have been forced to simplify the problem into a distance-constrained protein-protein docking task. To address the data issue, we develop a novel pseudo-data generation scheme that requires only binary protein-protein complexes. Its inference speed enables the large-scale screening of PROTAC designs, and computed properties of predicted structures achieve statistically significant correlations with published degradation activities. Targeted protein degradation is an emerging paradigm in rational drug design that induces the breakdown of "undruggable" proteins (Zhao et al., 2022). Proteolysis targeting chimeras (PROTACs) are small molecules that achieve this by simultaneously binding a protein of interest (POI) and a degradation-associated protein (e.g. In contrast to small molecule drugs, which attach to predefined sites on their protein targets, PROTACs operate by inducing a stable, ternary complex between themselves and two proteins which don't typically interact.