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

Target-based drug discovery is the dominant paradigm of drug discovery; however, a comprehensive evaluation of its real-world efficiency is lacking. Here, a manual systematic review of about 32000 articles and patents dating back to 150 years ago demonstrates its apparent inefficiency. Analyzing the origins of all approved drugs reveals that, despite several decades of dominance, only 9.4% of small-molecule drugs have been discovered through "target-based" assays. Moreover, the therapeutic effects of even this minimal share cannot be solely attributed and reduced to their purported targets, as they depend on numerous off-target mechanisms unconsciously incorporated by phenotypic observations. The data suggest that reductionist target-based drug discovery may be a cause of the productivity crisis in drug discovery. An evidence-based approach to enhance efficiency seems to be prioritizing, in selecting and optimizing molecules, higher-level phenotypic observations that are closer to the sought-after therapeutic effects using tools like artificial intelligence and machine learning.