Target-based Drug Discovery Is Inefficient: Discovery and “Off-target” Mechanisms of All Drugs

Abstract

For years, the low productivity of drug discovery has been a dilemma. More surprising has been the fact that our current productivity is far lower than 70 years ago. How could our ancestors, from thousands to a hundred years ago, discover drug-leads, like opioids, that we still rely on, yet we, with incomparably advanced technologies and knowledge, are desperate to do so? Based on massive evidence, I argue that the primary cause is the dominance of the reductionist “rational” drug discovery which tries to reduce the effects of molecules on highly complex phenotypes to single variables: affinity toward single hypothesized “targets.” Detailed analysis of the discovery origins of all currently used small-molecule drugs shows that, despite decades of dominance, only about 9% of them have “target-based” origins. More conclusively, even this minimal contribution depends on luckiness rather than sheer “rationality” as these “target-based” drugs have numerous “off-target” therapeutic mechanisms. These observations reveal the real-world inefficacy of “rational” drug discovery and imply that currently, powerful assets like artificial intelligence and deep learning are being employed by an ultimately inefficient paradigm.

Reductionism and proxy failure: From neuroscience to target-based drug discovery

“…For years, binding affinity to a target has been criticized as an overly simplistic proxy (Horrobin, 2003). Our recent analysis of the real-world efficiency of target-based drug discovery further substantiates these criticisms and reveals, based on significant evidence, the failure of this proxy (Sadri, 2023). The data reveal that, despite decades of utter dominance, only 9.4% of small-molecule-approved drugs have originated from target-based drug discovery.…”

“…Moreover, the analysis demonstrates that even this minor portion cannot be entirely attributed to target-based drug discovery, as their therapeutic effects are mediated by numerous mechanisms that are independent of the targets they have been discovered for (Sadri, 2023). This aligns perfectly with one of the factors identified by John et al to drive proxy failure: The human body and the therapeutic effects of molecules are highly complex and there are numerous “proxy-independent actions that lead to the goal” (target article, sect.…”

Empirical Analysis of Drug Targets for Nervous System Disorders

“…24 The fact that nearly two-thirds of GPCR-targeting drugs in the nervous system act on monoamine receptors signifies the important impact of phenotypic drug discovery approaches to uncovering druggable neurotherapeutic targets. 25 As shown in Table 1, the median CNS MPO score of 4.1 for nuclear receptor-targeting drugs is only slightly below the median scores of 4.4 for GPCR-and transporter-targeting drugs treating nervous system disorders, questioning the broader utility of the CNS MPO algorithm. This prompted us to analyze the six median transformed values (T0) constituting the CNS MPO score for these clusters.…”

Proteomic workflows for deep phenotypic profiling of 3D organotypic liver models

“…In support of these concerns, an extensive recent review of the origins of all approved drugs revealed that only 123 (10.7%) of all 1144 approved small‐molecule drugs have been discovered by target‐based discovery, whereas 1021(89.3%) were identified by phenotype‐based approaches. [ 36 ] The advent of organotypic human tissue models with physiologically relevant phenotypes allows for target‐agnostic discovery strategies with moderate‐to‐high throughput. However, to fully leverage the advances of such emerging phenotypic models, sensitive and scalable technologies are required that can provide accurate results despite the low inputs.…”