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Machine learning in targeted protein degradation drug design: a technical review of PROTACs and molecular glues 靶向蛋白质降解药物设计中的机器学习：PROTACs和分子胶的技术综述。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-01-01 Epub Date: 2025-11-27 DOI: 10.1016/j.drudis.2025.104563
Chieh-Te Lin , Ya-Ping Shiau , Chu-Chung Lin
{"title":"Machine learning in targeted protein degradation drug design: a technical review of PROTACs and molecular glues","authors":"Chieh-Te Lin ,&nbsp;Ya-Ping Shiau ,&nbsp;Chu-Chung Lin","doi":"10.1016/j.drudis.2025.104563","DOIUrl":"10.1016/j.drudis.2025.104563","url":null,"abstract":"<div><div>Targeted protein degradation (TPD) allows catalytic removal of disease-associated proteins by exploiting the ubiquitin–proteasome system (UPS). Proteolysis-targeting chimeras (PROTACs) and molecular glues represent two complementary TPD modalities, yet their rational design remains hindered by challenges in ternary complex formation, ligand discovery, and pharmacokinetic optimization. Recent machine learning (ML) advances address these barriers through predictive modeling, virtual screening, and generative design of degrader candidates. In this review, we summarize how ML is integrated across PROTACs and molecular glue development, including ternary complex prediction, linker and fragment design, degradation efficiency modeling, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) optimization. We also highlight emerging artificial intelligence (AI)-driven strategies for <em>de novo</em> glue discovery. Together, these innovations demonstrate how ML is accelerating degrader design and expanding the landscape of druggable targets.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104563"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Health care in the great people shortage: from arithmetic to design 保健在伟大的人的短缺：从算术到设计。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-01-01 Epub Date: 2025-12-04 DOI: 10.1016/j.drudis.2025.104564
Charles H. Jones
{"title":"Health care in the great people shortage: from arithmetic to design","authors":"Charles H. Jones","doi":"10.1016/j.drudis.2025.104564","DOIUrl":"10.1016/j.drudis.2025.104564","url":null,"abstract":"","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104564"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Biotechnology-based therapies for mitigation of pulmonary fibrosis: an update 缓解肺纤维化的生物技术疗法：最新进展
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-01-01 Epub Date: 2025-12-03 DOI: 10.1016/j.drudis.2025.104570
Satvik Sangai, Dhrumi Patel, Sarika Wairkar
{"title":"Biotechnology-based therapies for mitigation of pulmonary fibrosis: an update","authors":"Satvik Sangai,&nbsp;Dhrumi Patel,&nbsp;Sarika Wairkar","doi":"10.1016/j.drudis.2025.104570","DOIUrl":"10.1016/j.drudis.2025.104570","url":null,"abstract":"<div><div>Pulmonary fibrosis (PF) is a chronic interstitial lung disease that causes inflammation and scarring around the lung alveoli. This scarring is called fibrosis and leads to breathing difficulties in patients. The treatment for PF is currently limited to two drugs: nintedanib and pirfenidone. Their use is restricted owing to poor bioavailability and a few contraindications. Biotechnological advancements are leading to the investigation of targeted systems aimed at reversing alveolar damage and alleviating PF. This review provides key insights on biotechnology-based advancements for PF, namely monoclonal antibodies, peptides, nucleic acids and stem cell therapy. We also underscore the obstacles and prospective developments in biotechnology-derived therapeutics for PF.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104570"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145686648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The landscape of innovative oncology drug targets 创新肿瘤药物靶点的前景。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-01-01 Epub Date: 2025-12-04 DOI: 10.1016/j.drudis.2025.104571
Gui Yao , Leming Shi , Yuanting Zheng
{"title":"The landscape of innovative oncology drug targets","authors":"Gui Yao ,&nbsp;Leming Shi ,&nbsp;Yuanting Zheng","doi":"10.1016/j.drudis.2025.104571","DOIUrl":"10.1016/j.drudis.2025.104571","url":null,"abstract":"<div><div>The global oncology drug pipeline is characterized by a tension between the diversification of novel targets and a persistent concentration on a few validated ones. Our analysis of 5127 drugs against 1603 targets categorizes entities as ‘proven’ (10.4%), ‘in development’ (53.6%), or ‘not progressing well’ (36.1%). While single-target agents dominate, dual-target strategies, driven by bispecific antibodies, are the fastest-growing approach. The top 20 proven targets attract over 50 drugs each. Small molecules remain prevalent, but novel modalities are expanding. Clinical validation of a novel target requires a median of 8.0 years with a 22.3% success rate. The USA and China drive 62.7% of global development, with the USA leading in first-in-class (FIC) innovation and China’s role increasing since 2020.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104571"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Target product profile: An essential tool to deliver differentiated, patient-centered, and reimbursable medical products to treat substance use disorders 目标产品简介：提供差异化、以患者为中心和可报销的医疗产品以治疗物质使用障碍的基本工具。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-01-01 Epub Date: 2025-12-04 DOI: 10.1016/j.drudis.2025.104573
Tam Nguyen, Elena Koustova
{"title":"Target product profile: An essential tool to deliver differentiated, patient-centered, and reimbursable medical products to treat substance use disorders","authors":"Tam Nguyen,&nbsp;Elena Koustova","doi":"10.1016/j.drudis.2025.104573","DOIUrl":"10.1016/j.drudis.2025.104573","url":null,"abstract":"<div><div>Target product profiles (TPPs) guide medical product development by defining desired characteristics to address specific diseases or needs. By specifying safety, efficacy, usability, access, and differentiation, TPPs help to prioritize resources, surface challenges early, and reduce failure risk. Although common in drug development, TPPs are less often applied to substance use disorders (SUDs). This article shows how an SUD TPP should balance regulatory feasibility, clinical relevance, and commercial viability. We offer an example TPP for an aspirational opioid use disorder drug to test differentiation and market assumptions against existing therapies. TPPs focus attention beyond mechanistic novelty, clarifying distinct product attributes. Thoughtful TPP design increases the chance that a product will be safe, effective, accessible, reimbursable, and equitably distributable.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104573"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Decoding the plasma proteome: Advancing precision medicine in cardiovascular health 解码血浆蛋白质组：推进心血管健康精准医疗。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-01-01 Epub Date: 2025-12-12 DOI: 10.1016/j.drudis.2025.104584
Hector A. Cabrera-Fuentes , Elisa A. Liehn , Ebtesam A. Al-Suhaimi
{"title":"Decoding the plasma proteome: Advancing precision medicine in cardiovascular health","authors":"Hector A. Cabrera-Fuentes ,&nbsp;Elisa A. Liehn ,&nbsp;Ebtesam A. Al-Suhaimi","doi":"10.1016/j.drudis.2025.104584","DOIUrl":"10.1016/j.drudis.2025.104584","url":null,"abstract":"<div><div>The plasma proteome offers a dynamic window into human physiology, enabling biomarker discovery, target prioritization, and drug repurposing for cardiovascular disease. Advances in high-throughput platforms, protein quantitative trait loci mapping, and machine learning reveal pleiotropic proteins and candidate causal targets, but translation requires rigorous safeguards. We propose a rigorous, tiered pipeline: discovery, mandatory orthogonal confirmation (targeted mass spectrometry or independent immunoassay), genetic prioritization with colocalization and sensitivity analyses, tissue-resolved functional validation, and prospective clinical evaluation with regulatory qualification. Integration with multi-omics, diverse cohorts, and electronic health record-embedded implementation studies, using HL7 Fast Healthcare Interoperability Resources and the Observational Medical Outcomes Partnership Common Data Model, can accelerate reproducible, equitable development of precision cardiovascular therapeutics.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104584"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145754720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The next decade in cell and gene therapy 细胞和基因治疗的下一个十年。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-01-01 Epub Date: 2025-11-18 DOI: 10.1016/j.drudis.2025.104551
Sharon E. Phares, Colin M. Young, Katie I. Phillip, Mark R. Trusheim
{"title":"The next decade in cell and gene therapy","authors":"Sharon E. Phares,&nbsp;Colin M. Young,&nbsp;Katie I. Phillip,&nbsp;Mark R. Trusheim","doi":"10.1016/j.drudis.2025.104551","DOIUrl":"10.1016/j.drudis.2025.104551","url":null,"abstract":"<div><div>In the 8 years since the US Food and Drug Administration (FDA) approved the first durable cell and gene therapy (dCGT), there have been over 32 product-indication approvals, with many more products and indications in the pipeline. Using a novel multi-modal Markov chain Monte Carlo (MCMC)-based model, we estimate that, by 2034, the pipeline will yield ∼79 new product-indication approvals, an annual average of 29% year-over-year growth in treated patients, and US$28.8 billion in list price drug revenues, before any healthcare cost offsets, caregiving impacts, long-term social benefits, or other benefits from treating these additional patients.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104551"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Gaining regulatory acceptance for novel technologies in nonclinical drug development: A scoping review of its conceptualization in scientific literature 在非临床药物开发中获得新技术的监管认可：科学文献中对其概念化的范围审查。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-01-01 Epub Date: 2026-01-06 DOI: 10.1016/j.drudis.2026.104597
Ivar T. van der Zee , Joyce M. Hoek , Jarno Hoekman , Marie L. De Bruin
{"title":"Gaining regulatory acceptance for novel technologies in nonclinical drug development: A scoping review of its conceptualization in scientific literature","authors":"Ivar T. van der Zee ,&nbsp;Joyce M. Hoek ,&nbsp;Jarno Hoekman ,&nbsp;Marie L. De Bruin","doi":"10.1016/j.drudis.2026.104597","DOIUrl":"10.1016/j.drudis.2026.104597","url":null,"abstract":"<div><div>Although integrating novel technologies into nonclinical drug development can counteract declining R&amp;D success, their path to regulatory acceptance is often unclear and uncertain as they are not subject to a single, predictable regulatory approval framework like medicinal products. Existing literature on regulatory acceptance is mostly confined to specific technologies or regulatory pathways, hindering cross-domain learning. Therefore this scoping review develops a more context-agnostic understanding of regulatory acceptance by characterizing its commonalities across a range of technological and regulatory contexts. Our analysis of 54 articles found that regulatory acceptance can take on multiple forms, shaped by a particular scope (technological, contextual, and geographical) and formation process involving a driving need, gaining regulatory confidence, and interaction between actor groups. As technological specificity increases, the nature of the aforementioned elements shifts from broad discussions of potential to formal, evidence-based procedures. Understanding acceptance as a diverse process unified by core conceptual elements, rather than a single hurdle, provides a common language that cuts across technological domains and helps contextualize future research, thereby enabling regulators and developers to better integrate novel technologies in nonclinical drug development.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104597"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Corrigendum to “Reimagining medical affairs through strategic leadership in patient partnering healthcare” [Drug Discov. Today 31(1) (2026) 104558] “通过患者合作医疗的战略领导重新构想医疗事务”的勘误表[药物发现]。今天31(1)(2026)104558]。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-01-01 Epub Date: 2026-01-05 DOI: 10.1016/j.drudis.2025.104594
Sébastien Reig , Christel Becker
{"title":"Corrigendum to “Reimagining medical affairs through strategic leadership in patient partnering healthcare” [Drug Discov. Today 31(1) (2026) 104558]","authors":"Sébastien Reig ,&nbsp;Christel Becker","doi":"10.1016/j.drudis.2025.104594","DOIUrl":"10.1016/j.drudis.2025.104594","url":null,"abstract":"","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104594"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pharmacogenomics and mutation informatics: correlation of NAT2 mutations and isoniazid acetylation rate 药物基因组学和突变信息学：NAT2突变与异烟肼乙酰化率的相关性。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-01-01 Epub Date: 2025-11-26 DOI: 10.1016/j.drudis.2025.104561
Saroj Verma , Vaishali M. Patil , Uma Agarwal
{"title":"Pharmacogenomics and mutation informatics: correlation of NAT2 mutations and isoniazid acetylation rate","authors":"Saroj Verma ,&nbsp;Vaishali M. Patil ,&nbsp;Uma Agarwal","doi":"10.1016/j.drudis.2025.104561","DOIUrl":"10.1016/j.drudis.2025.104561","url":null,"abstract":"<div><div>Tuberculosis (TB) drug resistance poses a major global health challenge. The first-line antitubercular prodrug isoniazid (INH) is metabolized by <em>N</em>-acetyltransferase 2 (NAT2) and activated by catalase peroxidase (KatG) to inhibit enoyl-acyl carrier protein reductase (InhA) in the mycolic acid biosynthesis pathway. Genetic variations in NAT2 are associated with the formation of slow and fast acetylators, influencing drug efficacy and toxicity. Despite significant advances that have clarified key aspects of NAT2-mediated isoniazid metabolism, the complete spectrum of mechanisms governing isoniazid deactivation and their broader implications for treatment efficacy and resistance evolution remain to be fully elucidated. In this review, we discuss the pharmacokinetics (PK), pharmacodynamics (PD), dosing regimens, and pharmacogenomics of isoniazid, along with the role of artificial intelligence (AI)/machine learning (ML) in its personalized use. In addition, we analyze NAT2 mutations and their impact on acetylation rates using bioinformatics. These insights collectively advance our understanding of genotype-driven variability in isoniazid response, aiding the development of personalized therapy.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 1","pages":"Article 104561"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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