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

ABSTRACT: 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

SUBMITTER: Nordquist EB 

PROVIDER: S-EPMC12764353 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature