Mathematical Model for Covalent Proteolysis Targeting Chimeras: Thermodynamics and Kinetics Underlying Catalytic...

Area of Science:

• Chemical Biology
• Drug Discovery
• Biochemistry

Background:

• Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that induce targeted protein degradation by hijacking the ubiquitin-proteasome system (UPS).
• Conventional PROTACs rely on non-covalent interactions, which can be limited by weak binding affinities and suboptimal degradation kinetics.

Purpose of the Study:

• To develop a mechanistic mathematical model for irreversible covalent chemistry in targeted protein degradation (TPD).
• To analyze the thermodynamic and kinetic factors influencing ternary complex formation, ubiquitination, and degradation via the UPS.
• To explore the advantages of covalent modification of either the target protein of interest (POI) or the E3 ligase ligand.

Main Methods:

• Development of a mechanistic mathematical model for covalent TPD.
• Analysis of thermodynamic and kinetic parameters governing PROTAC-mediated degradation.
• Simulation of covalent interactions with POI and E3 ligase ligands.

Main Results:

• Covalency offers significant advantages in TPD by overcoming weak binary binding affinities and enhancing ternary complex formation kinetics.
• Irreversible covalent chemistry improves the overall degradation rates through the UPS.
• Covalent E3 PROTACs exhibit enhanced catalytic efficiency, particularly for rapidly turning-over target proteins.

Conclusions:

• Mechanistic modeling provides a theoretical framework for understanding covalent TPD.
• Covalent PROTACs represent a promising strategy to enhance the efficacy of targeted protein degradation.
• The study highlights the potential of covalent E3 PROTACs for degrading challenging, fast-turnover disease targets.