Linker-Driven Sampling of PROTAC-Induced Ternary Complexes.

Area of Science:

• Biochemistry
• Computational Chemistry
• Drug Discovery

Background:

• Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules inducing targeted protein degradation.
• Formation of the ternary complex (PROTAC-E3 ligase-protein of interest) is critical for PROTAC efficacy.
• Structural understanding of ternary complexes is vital for rational PROTAC design.

Purpose of the Study:

• To develop and validate a computational approach for sampling PROTAC-induced ternary complexes.
• To create an open-source software tool, TERNIFY, for streamlined ternary complex modeling.

Main Methods:

• A computational method reducing search space to linker conformational degrees of freedom.
• Validation using 40 cocrystal ternary complex structures.
• Testing with unbound protein structures for WDR5-PROTAC-VHL complexes.

Main Results:

• Achieved 97% and 50% retrospective success rates at Cα-RMSD thresholds of 10 and 4 Å, respectively.
• Predicted ternary complexes were within 7 Å of experimental structures for WDR5-PROTAC-VHL complexes.
• TERNIFY enables standalone ternary complex modeling without separate docking steps.

Conclusions:

• The computational approach effectively samples PROTAC-induced ternary complexes.
• TERNIFY provides an efficient, integrated workflow for ternary complex modeling.
• This tool facilitates rational PROTAC design and accelerates therapeutic development.