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

Abstract

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 targetbased 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.

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.…”

“…Interestingly, many antipsychotics discovered around the same time were later found to act on monoamine GPCRs in the nervous system . 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 …”

Exploring acetaminophen prodrugs and hybrids: a review

“…8 Structures of the reported carrier-linked O-modified APAP prodrugs. The 4-AC-APAP ( 17) and 4-AOC-APAP (18) series were first examined to be administered orally, while the prodrugs 19-26 were developed and studied as topical analgesics. In general, such phenols, when administered orally, exhibit poor bioavailability.…”

“…17 However, growing evidence that numerous small molecular drugs exert their effects through interactions with multiple targets improves drug research development that confronts the data reductionism approach. [18][19][20] Indeed, pain syndromes like neurodegenerative, cancer, lipid, and psychiatric disorders, metabolic/cardiovascular diseases, infectious diseases, and multifactorial natures cannot be efficiently cured by singletarget drug treatment. In this case, agents that can modulate multiple targets simultaneously (polypharmacology) are needed.…”

Recent advances of phenotypic screening strategies in the application of anti-influenza virus drug discovery

“…However, 90.6% of the small molecule drugs approved for marketing were found by phenotype-based screening strategies. In addition, data show that the number of approved first-in-class small-molecule drugs identified through phenotypic screening each year exceeds the number found through molecular target-based drug design methods, 36 and this strategy has been extensively applied to the research and development of antitumor drugs, 37 anti-inflammatory drugs, 38 antimalarial drugs 39,40 and antibacterial drugs. 41,42…”