Computational Modeling of PROTAC Ternary Complexes as Ensembles Using SILCS-xTAC.

Proteolysis targeting chimeras, or PROTACs, are an emerging class of drugs that offer the potential to develop therapeutics targeting "undruggable" proteins by stabilizing protein-protein interactions (PPI). This involves leveraging the physiological protein degradation mechanism based on ubiquitination through stabilization of target protein-E3 ubiquitin ligase PPI mediated by the PROTAC. Existing computational methods for ligand design are not typically designed for the ternary complex problem and may have limited accuracy or efficiency due to the use of either rigid docking or full molecular dynamics (MD) simulations. Here we present a method which uses SILCS (site identification by ligand competitive saturation) to address the challenge of designing ligands which stabilize PPI by using precomputed ensembles of (1) functional group affinity patterns, termed FragMaps, for efficient and accurate ligand docking and of (2) a collection of putative PPI dimer 3D structures as docking targets. SILCS simulations involving aqueous, multisolute grand canonical Monte Carlo (GCMC)/MD calculations generate the FragMaps for both the target and ligase proteins. An ensemble of PPI dimer conformations is generated using the FragMaps and then dimer FragMaps are generated by merging the two sets of FragMaps. PROTAC molecules are docked into the ensemble of dimer FragMaps, and the final scoring metrics are extracted from the most favorable ternary complex. The scoring metrics, including energetics, binding site geometry, and physicochemical terms, are weighted together to construct an activity score. The method is benchmarked on a diverse set of ternary crystal structures of different proteins and PROTACs, and the derived activity score shows modest correlation with DC