COMPASS: A Computational Pipeline to Identify Linkers Predicting Ubiquitinable PROTAC-Induced Ternary Complexes

Area of Science:

• Biochemistry
• Computational Biology
• Drug Discovery

Background:

• PROteolysis TArgeting Chimeras (PROTACs) are bifunctional molecules that induce targeted protein degradation.
• Rational PROTAC design is challenging due to complex ternary structures and linker roles.

Purpose of the Study:

• Introduce COMPASS, a computational pipeline for screening PROTAC linker libraries.
• Assess ternary complex formation and ubiquitination potential for PROTAC design.

Main Methods:

• COMPASS uses structure-based screening to evaluate linker libraries.
• It functions as a negative filter to eliminate non-productive linkers.
• Benchmarking involved 20 crystallographic structures and retrospective validation on 112 PROTACs across 8 systems.

Main Results:

• COMPASS achieved <6 Å Cα-RMSD across 20 crystallographic structures.
• Retrospective validation showed 93% recall for degradation endpoints.
• The method excels in linker-geometry-limited scenarios.

Conclusions:

• COMPASS enhances PROTAC design by computationally screening linkers.
• It effectively predicts ternary complex formation and degradation potential.
• This tool complements existing methods by addressing linker geometry limitations.