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Translational PBPK/PD modeling in drug discovery: A CRO perspective 药物发现中的翻译PBPK/PD建模：一个CRO视角。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-08 DOI: 10.1016/j.drudis.2025.104427
Simone Esposito, David Cebrián
{"title":"Translational PBPK/PD modeling in drug discovery: A CRO perspective","authors":"Simone Esposito,&nbsp;David Cebrián","doi":"10.1016/j.drudis.2025.104427","DOIUrl":"10.1016/j.drudis.2025.104427","url":null,"abstract":"<div><div>The use of translational physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) modeling has become a standard practice in drug discovery, providing advanced data integration accounting for species-specific physiology and target pharmacology. This paper provides a preclinical contract research organization (CRO) perspective on the applications, benefits, and challenges of translational PBPK/PD modeling approaches in integrated drug discovery (IDD) collaborations. We also describe how PBPK/PD approaches have impacted the role of the drug metabolism and pharmacokinetics project representative (DPR) within CROs. We propose that adopting translational PBPK/PD approaches enhances the sponsor–CRO IDD partnership by fostering data-driven project decision-making and optimizing the use of resources.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 8","pages":"Article 104427"},"PeriodicalIF":6.5,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606991","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
Advancements and challenges in using AI for biomarker detection in early Alzheimer’s disease 人工智能用于早期阿尔茨海默病生物标志物检测的进展和挑战。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-01 DOI: 10.1016/j.drudis.2025.104415
Iman Beheshti , Benedict C. Albensi , Alex Freitas , Taravat Ghafourian
{"title":"Advancements and challenges in using AI for biomarker detection in early Alzheimer’s disease","authors":"Iman Beheshti ,&nbsp;Benedict C. Albensi ,&nbsp;Alex Freitas ,&nbsp;Taravat Ghafourian","doi":"10.1016/j.drudis.2025.104415","DOIUrl":"10.1016/j.drudis.2025.104415","url":null,"abstract":"<div><div>The rapid growth in Alzheimer’s disease (AD) research has led to an unprecedented accumulation of biomedical and clinical data, including longitudinal patient datasets and comprehensive observational cohort databases comprising clinical, biomedical, neuroimaging and lifestyle data. Expert use of machine learning algorithms is indispensable in order to realize the full potential of the data for diagnosis and drug target discovery. Here, we provide an overview of the biomedical and neuroimaging measures for AD diagnosis and staging. We then critically review the application of machine learning (classification) methods to AD data and provide insight for future improvements and research directions. Future research should aim to improve interpretability, accessibility and thorough validation of the models, enabling translation into clinical applications.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 7","pages":"Article 104415"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367757","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
Unraveling the potential of diffusion models in small-molecule generation 揭示扩散模型在小分子生成中的潜力。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-01 DOI: 10.1016/j.drudis.2025.104413
Peining Zhang , Daniel Baker , Minghu Song , Jinbo Bi
{"title":"Unraveling the potential of diffusion models in small-molecule generation","authors":"Peining Zhang ,&nbsp;Daniel Baker ,&nbsp;Minghu Song ,&nbsp;Jinbo Bi","doi":"10.1016/j.drudis.2025.104413","DOIUrl":"10.1016/j.drudis.2025.104413","url":null,"abstract":"<div><div>Generative artificial intelligence (AI) presents chemists with novel ideas for drug design and facilitates the exploration of vast chemical spaces. As an emerging tool, diffusion models (DMs) have recently attracted great attention in drug research and development (R&amp;D). Here, we comprehensively review the latest advances in, and applications of, DMs in molecular generation. We introduce the theoretical principles of DMs and then categorize various DM-based molecular generation methods according to their mathematical and chemical applications. We also examine the performance of these models on benchmark datasets, with a particular focus on comparing the generation performance of existing 3D methods. Finally, we conclude by emphasizing current challenges and suggesting future research directions to fully exploit the potential of DMs in drug discovery.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 7","pages":"Article 104413"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493214","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
Antimicrobial Resistance: From Ukraine to Gaza 抗生素耐药性：从乌克兰到加沙。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-01 DOI: 10.1016/j.drudis.2025.104411
Santanu Datta
{"title":"Antimicrobial Resistance: From Ukraine to Gaza","authors":"Santanu Datta","doi":"10.1016/j.drudis.2025.104411","DOIUrl":"10.1016/j.drudis.2025.104411","url":null,"abstract":"","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 7","pages":"Article 104411"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339718","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
Targeting mutant EGFR in non-small cell lung cancer in the context of cell adaptation and resistance 靶向EGFR突变体在非小细胞肺癌中的细胞适应性和耐药性研究
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-01 DOI: 10.1016/j.drudis.2025.104407
Selene K. Roberts , Ioannis Galgadas , David T. Clarke , Laura C. Zanetti-Domingues , Francesco L. Gervasio , Marisa L. Martin-Fernandez
{"title":"Targeting mutant EGFR in non-small cell lung cancer in the context of cell adaptation and resistance","authors":"Selene K. Roberts ,&nbsp;Ioannis Galgadas ,&nbsp;David T. Clarke ,&nbsp;Laura C. Zanetti-Domingues ,&nbsp;Francesco L. Gervasio ,&nbsp;Marisa L. Martin-Fernandez","doi":"10.1016/j.drudis.2025.104407","DOIUrl":"10.1016/j.drudis.2025.104407","url":null,"abstract":"<div><div>Activating mutations in the catalytic kinase domain of the epidermal growth factor receptor (EGFR) are crucial drivers of non-small cell lung cancer (NSCLC). Our understanding of the structural changes induced by such mutations has evolved alongside the rational design of targeted tyrosine kinase inhibitors (TKIs), leading to improved anti-tumor responses through appropriate patient stratification. However, challenges remain, including a growing number of therapy adaptation mechanisms and acquired resistance, which are further complicated by the intricate signaling networks of EGFR. Here, we review the rational development and targeting of EGFR-TKIs in the context of TKI-induced cellular death, adaptation, resistance, and eventual clinical failure, to provide a birds-eye view of this highly multidisciplinary field. We end by proposing new approaches based on our developing understanding of the quaternary structure of EGFR, which leverage <em>in situ</em> oligomer architectures to develop therapies that modulate EGFR oligomer-specific interactions and exploit weaknesses in its downstream signaling network to overcome resistance.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 7","pages":"Article 104407"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336134","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
Translational PK/PD: a retrospective analysis of performance and impact from a drug portfolio 翻译PK/PD：从药物组合的性能和影响的回顾性分析。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-01 DOI: 10.1016/j.drudis.2025.104417
Rasmus Jansson-Löfmark , Markus Fridén , Lassina Badolo , Christine Ahlström , Ian Gurrell , Menelas N. Pangalos , Rhys DO Jones
{"title":"Translational PK/PD: a retrospective analysis of performance and impact from a drug portfolio","authors":"Rasmus Jansson-Löfmark ,&nbsp;Markus Fridén ,&nbsp;Lassina Badolo ,&nbsp;Christine Ahlström ,&nbsp;Ian Gurrell ,&nbsp;Menelas N. Pangalos ,&nbsp;Rhys DO Jones","doi":"10.1016/j.drudis.2025.104417","DOIUrl":"10.1016/j.drudis.2025.104417","url":null,"abstract":"<div><div>Attrition in drug development continues to be dominated by failure in clinical mid-stage proof-of-concept studies. Successfully demonstrating proof-of-mechanism (PoM) has been reported to be a key factor to improve clinical success. Accurate prediction and testing of PoM are crucial. This analysis of AstraZeneca’s portfolio assesses the role of translational PK/PD modelling in predicting clinical PoM. It has found that 83% of compounds had drug exposure–response within a threefold prediction accuracy. Notably, projects with robust PK/PD packages achieved an 85% success rate in PoM, compared with 33% for those with basic packages. This highlights how translational PK/PD modelling can significantly enhance success rates for drugs entering clinical trials.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 7","pages":"Article 104417"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493213","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
Exploring nucleotide and non-nucleotide cGAS-STING agonists: Therapeutic applications and future directions in cancer immunotherapy 探索核苷酸和非核苷酸cGAS-STING激动剂：在癌症免疫治疗中的治疗应用和未来方向。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-01 DOI: 10.1016/j.drudis.2025.104412
Abhishek Ghara , Gurubasavaraja Swamy Purawarga Matada , Payel Pramanick , Uday Raj Sharma , Prasad Sanjay Dhiwar
{"title":"Exploring nucleotide and non-nucleotide cGAS-STING agonists: Therapeutic applications and future directions in cancer immunotherapy","authors":"Abhishek Ghara ,&nbsp;Gurubasavaraja Swamy Purawarga Matada ,&nbsp;Payel Pramanick ,&nbsp;Uday Raj Sharma ,&nbsp;Prasad Sanjay Dhiwar","doi":"10.1016/j.drudis.2025.104412","DOIUrl":"10.1016/j.drudis.2025.104412","url":null,"abstract":"<div><div>The STING (stimulator of interferon genes) pathway plays a crucial role in immune defense against carcinoma. This review highlights its role in antigen response, tumor infiltration, and T-cell activation. Despite the promise of STING agonists, challenges like drug stability and toxicity hinder clinical success. Nanoparticle-based drug delivery and combinatorial strategies offer potential solutions to enhance efficacy and minimize resistance. Ongoing research focuses on developing novel STING agonists for improved cancer treatment. This article explores the pathway’s immunological significance, biochemical mechanisms, and pharmacological hurdles while discussing strategies to enhance the potency, safety, and therapeutic potential of STING-targeted therapies.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 7","pages":"Article 104412"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367758","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
Collaborative innovation during the drug discovery and development process 药物发现和开发过程中的协同创新。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-01 DOI: 10.1016/j.drudis.2025.104409
Xue Wu , Mirjam Knockaert , Paolo Blasi
{"title":"Collaborative innovation during the drug discovery and development process","authors":"Xue Wu ,&nbsp;Mirjam Knockaert ,&nbsp;Paolo Blasi","doi":"10.1016/j.drudis.2025.104409","DOIUrl":"10.1016/j.drudis.2025.104409","url":null,"abstract":"<div><div>Given the complexity and resource-intensive nature of the drug discovery and development process, breakthrough innovations often stem from multidisciplinary collaborations. This systematic literature review examines collaborative innovation within this process, analyzing current practices and identifying future research directions. The review used an evidence-based approach, retrieving 737 papers through a Web of Science “All Databases” search, and ultimately selecting 74 articles for discussion. The articles were categorized according to the initiation, implementation, and closure phases of collaborative innovation, and were classified into homogeneous and heterogeneous collaborations. Using this framework, we systematically reviewed the existing knowledge, with a particular focus on how collaborative innovation can be successfully initiated and implemented, and how it can generate positive outcomes for drug research.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 7","pages":"Article 104409"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293050","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
A step closer to medicinal product harmonisation: EMA PMS becomes the next focus of IDMP efforts 离药品统一又近了一步：EMA PMS成为IDMP工作的下一个重点。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-07-01 DOI: 10.1016/j.drudis.2025.104410
Michiel Stam
{"title":"A step closer to medicinal product harmonisation: EMA PMS becomes the next focus of IDMP efforts","authors":"Michiel Stam","doi":"10.1016/j.drudis.2025.104410","DOIUrl":"10.1016/j.drudis.2025.104410","url":null,"abstract":"","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 7","pages":"Article 104410"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309376","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
Computational approaches to DMPK: A realistic assessment of current methods and their practical impact. Part I: Physicochemical and in vitro properties DMPK的计算方法：对当前方法及其实际影响的现实评估。第一部分：理化和体外特性。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2025-06-30 DOI: 10.1016/j.drudis.2025.104422
Koichi Handa , Mariko Hirano , Michiharu Kageyama , Andreas Bender
{"title":"Computational approaches to DMPK: A realistic assessment of current methods and their practical impact. Part I: Physicochemical and in vitro properties","authors":"Koichi Handa ,&nbsp;Mariko Hirano ,&nbsp;Michiharu Kageyama ,&nbsp;Andreas Bender","doi":"10.1016/j.drudis.2025.104422","DOIUrl":"10.1016/j.drudis.2025.104422","url":null,"abstract":"<div><div>Artificial intelligence and computational approaches have received considerable interest in recent years, and here we assess their real-world utility in drug discovery projects. We review recent <em>in silico</em> models in the area of drug metabolism and pharmacokinetics (DMPK), especially for physicochemical properties (pKa and logD) and <em>in vitro</em> assays [solubility (DMSO, Dried-DMSO, Powder), permeability (PAMPA, Caco-2, MDCK), metabolic stability (liver microsome, hepatocyte), and protein binding (plasma, microsome, brain)]. We discuss which are currently fit for purpose (and which are not), bridging both computational and experimental aspects in the early drug discovery stages. The review includes diverse aspects of obtaining data and model generation, as well as modeler/experimentalist interplay.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 8","pages":"Article 104422"},"PeriodicalIF":6.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551549","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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