PROTAC-DB 2.0: an updated database of PROTACs

Area of Science:

• Biochemistry
• Drug Discovery
• Molecular Biology

Background:

• Proteolysis targeting chimeras (PROTACs) leverage the ubiquitin-proteasome system for targeted protein degradation, offering a novel therapeutic approach for previously undruggable targets.
• The field has rapidly advanced from academic research to clinical applications, with over 10 PROTACs currently in clinical trials.
• Despite progress, challenges remain in designing potent PROTACs with optimal drug-like properties.

Purpose of the Study:

• To present PROTAC-DB 2.0, an expanded and updated online database for PROTACs.
• To provide a comprehensive repository of structural and experimental data for PROTACs and their components.
• To facilitate the design and analysis of PROTACs through enhanced data and predictive tools.

Main Methods:

• The database was updated, significantly expanding the number of entries for PROTACs, warheads, linkers, and E3 ligands.
• Predicted ternary complex structures were generated using the PROTAC-Model method for PROTACs with high degradation potential.
• A new filtering strategy based on E3 ligases was implemented to enhance data analysis capabilities.

Main Results:

• PROTAC-DB 2.0 now contains 3270 PROTAC entries, a 96% increase from the previous version.
• The database includes over 360 warheads, 1500 linkers, and 80 E3 ligands.
• Predicted ternary complex structures and an E3 ligase-based filtering strategy were added to facilitate research.

Conclusions:

• PROTAC-DB 2.0 serves as a valuable, expanded resource for researchers in the field of targeted protein degradation.
• The database and its new features support the ongoing development of novel PROTAC-based therapeutics.
• This updated repository aids in overcoming challenges in PROTAC design and accelerates the discovery of new drug candidates.