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.