HADDOCK-Guided modeling and molecular simulations of cereblon-based ternary complexes: Development of novel PROTACs for Ataxia telangiectasia and RAD3-Related (ATR) kinase.

Proteolysis-targeting chimeras (PROTACs) offer a novel therapeutic strategy for degrading disease-causing proteins, but designing effective degraders remains challenging. PROTACs function by inducing a ternary complex between the target protein and an E3 ligase, requiring structural insights for rational design. Key factors include linker optimization, attachment points, and warhead refinement. Computational approaches, particularly protein-protein docking, are essential for modeling ternary complexes and predicting critical interactions. However, existing docking methods struggle with cereblon (CRBN)-based ternary complexes. To address this, we introduce a computational approach combining HADDOCK protein-protein docking with induced fit PROTAC docking. Validated against 26 crystal structures from the Protein Data Bank (PDB), this method demonstrated high accuracy, especially for CRBN-based complexes. Additionally, molecular dynamics (MD) simulations of CRBN-BRD4-BD1 complexes (PDB IDs 6BN7, 6BOY) provided insights into complex stability through buried surface area and radius of gyration calculations. This validated approach was then applied to five Ataxia telangiectasia and RAD3-related (ATR) kinase PROTACs, enabling modeling in the absence of experimental structures. Our method provides a robust framework for optimizing and designing novel PROTACs targeting diverse proteins.