Target-based Drug Discovery Is Inefficient: Discovery and “Off-target” Mechanisms of All Drugs
Arash Sadri · 2022
Target-based drug discovery has dominated drug discovery for decades. Despite criticisms and evidence against its reductionism, there lacks a comprehensive assessment of its real-world efficiency. Here, its inefficiency is shown by a massive corpus of evidence from a manual and systematic review of about 32000 articles and patents dating back to 150 years ago. Discovery origins of all approved drugs showed, despite decades of dominance, only 9.4% are small molecules discovered by “target-based” assays. Analysis of therapeutic mechanisms showed that the therapeutic effects of even this minimal share are not reducible to their “targets” and are indebted to numerous off-targets unconsciously incorporated by phenotypic observations. While highlighting reductionist target-based drug discovery as a main reason for drug discovery’s low productivity, the data suggests that an evidence-based approach to increasing efficiency is to maximally prioritize in selecting and optimizing molecules, higher-level phenotypic observations that are closer to the sought therapeutic effect.