Rational Prediction of PROTAC-compatible Protein-Protein Interfaces by Molecular Docking

Abstract Proteolysis targeting chimeras (PROTACS) are heterobifunctional ligands that mediate the interaction between a protein target and an E3 ligase, resulting in a ternary complex whose interaction with the ubiquitination machinery leads to target degradation. This technology is emerging as an exciting new avenue for therapeutic development, with several PROTACS currently undergoing clinical trials targeting cancer. Here, we describe a general and computationally efficient methodology combining restraint-based docking, energy-based rescoring, and a filter based on minimal solvent-accessible surface distance to produce PROTAC-compatible PPIs suitable for when there is no a priori known PROTAC ligand. In a benchmark employing a manually curated dataset of 13 ternary complex crystals, we achieved accuracy of 92% when starting from bound structures, and 77% when starting from unbound structures, respectively. Our method only requires that the ligand-bound structures of the monomeric forms of the E3 ligase and target proteins be given to run, making it general, accurate and highly efficient, with the ability to impact early stage PROTAC-based drug design campaigns where no structural information about the ternary complex structure is available.