Is Target-Based Drug Discovery Efficient? Discovery and "Off-Target" Mechanisms of All Drugs

Area of Science:

• Drug discovery and development
• Pharmacology
• Medicinal chemistry

Background:

• Target-based drug discovery is the predominant approach in pharmaceutical research.
• A comprehensive evaluation of its real-world efficiency and productivity is lacking.
• The productivity crisis in drug discovery necessitates a re-evaluation of current methodologies.

Purpose of the Study:

• To evaluate the real-world efficiency of target-based drug discovery.
• To analyze the origins of approved small-molecule drugs.
• To identify alternative strategies for enhancing drug discovery productivity.

Main Methods:

• A manual systematic review of approximately 32,000 articles and patents spanning 150 years.
• Analysis of the discovery origins for all approved drugs.
• Comparative analysis of target-based versus phenotypic drug discovery approaches.

Main Results:

• Only 9.4% of approved small-molecule drugs were discovered using target-based assays, despite decades of dominance.
• The therapeutic effects of target-based drugs often rely on uncharacterized off-target mechanisms observed phenotypically.
• Reductionist target-based approaches may contribute to the drug discovery productivity crisis.

Conclusions:

• The efficiency of target-based drug discovery is questionable, highlighting limitations of the reductionist approach.
• Phenotypic drug discovery, which considers holistic effects, offers a potentially more efficient strategy.
• Integrating artificial intelligence and machine learning with phenotypic observations can enhance molecule selection and optimization for improved drug discovery outcomes.