{"title":"基于靶点的药物发现有效吗?所有药物的发现和“脱靶”机制","authors":"Arash Sadri*, ","doi":"10.1021/acs.jmedchem.2c01737","DOIUrl":null,"url":null,"abstract":"<p >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.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Is Target-Based Drug Discovery Efficient? Discovery and “Off-Target” Mechanisms of All Drugs\",\"authors\":\"Arash Sadri*, \",\"doi\":\"10.1021/acs.jmedchem.2c01737\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >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.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2023-09-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01737\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01737","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
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.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.