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

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Biology

Background:

• Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that induce targeted protein degradation.
• PROTACs are a promising therapeutic strategy, with several candidates in clinical trials for cancer treatment.

Purpose of the Study:

• To develop a general and computationally efficient methodology for predicting PROTAC-compatible protein-protein interfaces (PPIs).
• To enable PROTAC design when no prior structural information of the ternary complex is available.

Main Methods:

• The methodology combines restraint-based docking, energy-based rescoring, and a minimal solvent-accessible surface distance filter.
• It requires only the ligand-bound structures of the monomeric E3 ligase and target proteins.

Main Results:

• The method achieved 92% accuracy starting from bound structures and 77% accuracy from unbound structures in a benchmark of 13 ternary complex crystals.
• The approach is general, accurate, and highly efficient.

Conclusions:

• This computational method significantly impacts early-stage PROTAC drug design by providing accurate PPI predictions.
• It facilitates the development of novel PROTAC-based therapeutics even without existing ternary complex structural data.