Integrating AI into next-generation PROTAC Engineering: a comprehensive toolkit for rational PROTAC design

Area of Science:

• Biochemistry and Medicinal Chemistry
• Drug Discovery and Development
• Computational Chemistry

Background:

• Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that induce targeted protein degradation.
• PROTACs offer an event-driven mechanism for degrading disease-associated proteins, overcoming limitations of traditional inhibitors.
• Challenges including poor pharmacokinetics and high molecular weight hinder PROTAC clinical application.

Purpose of the Study:

• To review the limitations of conventional computational methods in PROTAC research.
• To explore emerging AI-driven tools for various aspects of PROTAC development.
• To highlight current challenges and future directions in AI-assisted PROTAC design.

Main Methods:

• Review of existing literature on computational methods and AI applications in PROTAC research.
• Identification and categorization of AI tools for target selection, linker generation, activity prediction, degradability assessment, ternary complex modeling, PROTAC generation, and ADME property estimation.
• Analysis of challenges associated with AI in PROTAC development.

Main Results:

• AI-driven technologies are being utilized to generate novel, chemically valid PROTACs, overcoming limitations of traditional methods.
• Specific AI tools demonstrate potential in target selection (DeepUSI, DrugnomeAI), linker generation (AIMLinker, DiffLinker), activity prediction (AI-DPAPT, DeepPROTAC), and more.
• AI accelerates the design and optimization of PROTACs for improved therapeutic potential.

Conclusions:

• AI significantly enhances PROTAC research, offering solutions to challenges in drug discovery and development.
• Addressing data scarcity, reproducibility, and model generalizability is crucial for advancing AI in PROTACs.
• Hybrid or integrated AI approaches are needed to overcome current limitations and fully realize the potential of AI-driven PROTAC design.