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Benign-by-design chemistry: Reinventing ligand-based drug design at the edge of AI. 设计良性化学：在人工智能的边缘重塑基于配体的药物设计。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-05-07 DOI: 10.1016/j.drudis.2026.104691
Edgar López-López, Pamela I Hernández-Estrada, Angel N Toto-Vazquez, Diana V Ávila-Martínez, Ola Spjuth, José L Medina-Franco
{"title":"Benign-by-design chemistry: Reinventing ligand-based drug design at the edge of AI.","authors":"Edgar López-López, Pamela I Hernández-Estrada, Angel N Toto-Vazquez, Diana V Ávila-Martínez, Ola Spjuth, José L Medina-Franco","doi":"10.1016/j.drudis.2026.104691","DOIUrl":"https://doi.org/10.1016/j.drudis.2026.104691","url":null,"abstract":"<p><p>Ligand-based drug design (LBDD) has long driven therapeutic innovation; however, its traditional potency-centered paradigm often oversimplifies biological complexity. Advances in artificial intelligence (AI) now enable multiobjective strategies that integrate polypharmacology, safety and environmental sustainability. Despite this progress, a unified framework that systematically incorporates these dimensions within AI-augmented LBDD is lacking. Here, we propose that embedding benign-by-design principles into multiobjective optimization can enable the proactive mitigation of toxicity, off-target effects and ecological impact from the early design and discovery stages. This shift redefines LBDD as a complexity-aware and ethically grounded discipline capable of delivering safer and more sustainable therapeutics. Accordingly, the primary objective of this review is to outline a unifying framework for AI-enabled LBDD that moves beyond potency-centered optimization by integrating efficacy, safety, sustainability and societal impact.</p>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":" ","pages":"104691"},"PeriodicalIF":7.5,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863224","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
Biomedical applications of mannan conjugates. 甘露聚糖缀合物的生物医学应用。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-05-07 DOI: 10.1016/j.drudis.2026.104690
Ariba Khan, Jai Vengurlekar, Amol Gholap, Navnath Hatvate
{"title":"Biomedical applications of mannan conjugates.","authors":"Ariba Khan, Jai Vengurlekar, Amol Gholap, Navnath Hatvate","doi":"10.1016/j.drudis.2026.104690","DOIUrl":"https://doi.org/10.1016/j.drudis.2026.104690","url":null,"abstract":"<p><p>Mannans are a major component of gymnosperm wood and are found in the seed of various non-leguminous plants {AuQ: Edit OK?}. This group of polymers have received great attention because of their physico-chemical properties, such as their viscosity, polymerization, solubility, and gelling ability, as well as their biocompatibility, biodegradability, and non-toxicity. Mannans can be conjugated with different molecules, including drugs, carriers, and biomolecules such as proteins and antigens, in order to enhance the efficacy and potency of these molecules. Such conjugates are fabricated by methods such as reductive amination, aminoxyligation, carbodiimide coupling, mannosylation, and cyanylation. This review highlights different strategies for the synthesis of mannans, the various fabrication methods, and the wide applications of mannan conjugates in various fields such as tissue engineering, diagnostics, vaccine delivery, therapeutics, and biomedicine.</p>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":" ","pages":"104690"},"PeriodicalIF":7.5,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863250","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
Ligand trapping as a key mechanism governing drug residence time, binding affinity, and potency. 配体捕获是控制药物停留时间、结合亲和力和效力的关键机制。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-05-06 DOI: 10.1016/j.drudis.2026.104694
Danislav S Spassov
{"title":"Ligand trapping as a key mechanism governing drug residence time, binding affinity, and potency.","authors":"Danislav S Spassov","doi":"10.1016/j.drudis.2026.104694","DOIUrl":"https://doi.org/10.1016/j.drudis.2026.104694","url":null,"abstract":"<p><p>Estimating binding affinity and potency is vital for the design of high-affinity compounds. Protein-ligand interactions are accompanied by conformational changes, resulting in complex kinetic behavior that influences drug activity and potency. From the general kinetic scheme of protein-ligand interactions, four limiting mechanisms emerge: lock-and-key, induced fit (IF), conformational selection (CS), and ligand trapping (LT). Together, these mechanisms define key structural and kinetic principles relevant to drug discovery. Here, I discuss the principles governing binding and dissociation, with particular emphasis on LT and its influence on dissociation kinetics. LT is the underlying mechanism that leads to slow dissociation and long residence times. As such, this mechanism is crucial for understanding the pharmacological activity of drugs that exhibit these properties and for guiding their rational design.</p>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":" ","pages":"104694"},"PeriodicalIF":7.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855523","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 and Medical Research in Australia I: A Long-term Investment that Drives Innovation and Endogenous Growth. 澳大利亚的健康和医学研究I：推动创新和内生增长的长期投资。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-05-06 DOI: 10.1016/j.drudis.2026.104692
Levon M Khachigian
{"title":"Health and Medical Research in Australia I: A Long-term Investment that Drives Innovation and Endogenous Growth.","authors":"Levon M Khachigian","doi":"10.1016/j.drudis.2026.104692","DOIUrl":"https://doi.org/10.1016/j.drudis.2026.104692","url":null,"abstract":"","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":" ","pages":"104692"},"PeriodicalIF":7.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855531","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 and Medical Research in Australia II: A Golden Egg Opportunity Too Valuable to Underfund. 澳大利亚的健康和医学研究II：一个金蛋机会太宝贵了，资金不足。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-05-05 DOI: 10.1016/j.drudis.2026.104693
Levon M Khachigian
{"title":"Health and Medical Research in Australia II: A Golden Egg Opportunity Too Valuable to Underfund.","authors":"Levon M Khachigian","doi":"10.1016/j.drudis.2026.104693","DOIUrl":"10.1016/j.drudis.2026.104693","url":null,"abstract":"","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":" ","pages":"104693"},"PeriodicalIF":7.5,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831717","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
Artificial protein scaffolds for human therapeutics: drug discovery and delivery strategies. 用于人类治疗的人工蛋白质支架：药物发现和递送策略。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-05-05 DOI: 10.1016/j.drudis.2026.104689
Amol D Gholap, Pankaj Khuspe, Abdelwahab Omri
{"title":"Artificial protein scaffolds for human therapeutics: drug discovery and delivery strategies.","authors":"Amol D Gholap, Pankaj Khuspe, Abdelwahab Omri","doi":"10.1016/j.drudis.2026.104689","DOIUrl":"10.1016/j.drudis.2026.104689","url":null,"abstract":"<p><p>Artificial protein scaffolds have emerged as next-generation biologics that address key limitations of monoclonal antibodies, including large size, poor tissue penetration and complex manufacturing. This review discusses major scaffold classes, including antibody-derived and non-antibody platforms, and highlights engineering strategies, such as rational design, library screening, AI-driven optimization and multi-specific formats. Their expanding roles in drug discovery, including target validation, hit identification, mechanistic studies and companion diagnostics, are examined alongside therapeutic applications in oncology, immunotherapy, infectious diseases, metabolic disorders and CNS disorders. The article further outlines scaffold-enabled drug delivery strategies, conjugation approaches and clinical progress. Key translational challenges, such as immunogenicity, pharmacokinetics and manufacturing, are discussed, along with future opportunities to integrate artificial intelligence and precision medicine to advance scaffold-based therapeutics.</p>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":" ","pages":"104689"},"PeriodicalIF":7.5,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831720","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
Accelerating the orphan GPCR pipeline: GPR149 as a case study in dual-domain target validation 加速孤儿GPCR管道：GPR149作为双结构域靶标验证的案例研究。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-05-01 Epub Date: 2026-04-20 DOI: 10.1016/j.drudis.2026.104678
Michael A.S. Guth
{"title":"Accelerating the orphan GPCR pipeline: GPR149 as a case study in dual-domain target validation","authors":"Michael A.S. Guth","doi":"10.1016/j.drudis.2026.104678","DOIUrl":"10.1016/j.drudis.2026.104678","url":null,"abstract":"<div><div>High failure rates in drug development for central nervous system (CNS) and metabolic diseases frequently stem from a lack of knowledge about their selected drug targets. With unknown ligand chemistry, orphan G-protein-coupled receptors (GPCRs) represent high-risk, but high-potential, high-reward opportunities for pharmaceutical development. Here, I describe a framework for de-risking such targets using GPR149 as a prototype. The Four-Pillar Framework, combining high-throughput screening, cryo-electron microscopy (EM), artificial intelligence (AI)-driven chemistry, and parallel circuit validation, unexpectedly revealed the dual metabolic (weight loss) and CNS applications of GPR149. In the process, a seemingly intractable orphan receptor has become a development asset with blockbuster potential. This methodology offers a reproducible template for exploring the ‘dark GPCRome’, particularly for disorders in which metabolic dysfunction and CNS comorbidities co-present in real-world patient populations.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 3","pages":"Article 104678"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758632","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
Regulatory innovation for drug repurposing: Ten proposals to accelerate access and safety 药物再利用的监管创新：加速可及性和安全性的十项建议。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-05-01 Epub Date: 2026-04-24 DOI: 10.1016/j.drudis.2026.104682
Sara Pintado , Adelaide Fernandes , Esther A.M. Bührman , Joanna IntHout , Sofia Oliveira-Martins
{"title":"Regulatory innovation for drug repurposing: Ten proposals to accelerate access and safety","authors":"Sara Pintado ,&nbsp;Adelaide Fernandes ,&nbsp;Esther A.M. Bührman ,&nbsp;Joanna IntHout ,&nbsp;Sofia Oliveira-Martins","doi":"10.1016/j.drudis.2026.104682","DOIUrl":"10.1016/j.drudis.2026.104682","url":null,"abstract":"<div><div>Despite increasing efforts and incentives to address the critical lack of treatments for rare diseases, a substantial gap persists between patient needs and available therapies. Drug repurposing is a promising strategy in this field; nevertheless, it has not yet translated into a substantial increase in approved medicines. Although several EU regulatory pathways exist, none is tailored to drug repurposing, resulting in a complex landscape, particularly for nonprofit organisations. While there is no silver bullet, this article presents ten regulatory proposals to foster dialogue with decision-makers to tackle bottlenecks in areas of unmet medical need through a collaborative model with aligned incentives for all stakeholders. These proposals are based on published literature and the authors’ experience in the SIMPATHIC project.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 3","pages":"Article 104682"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758575","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 statewide multi-institutional model that de-risks academic drug discovery 一个全州范围的多机构模式，降低学术药物发现的风险。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-05-01 Epub Date: 2026-04-29 DOI: 10.1016/j.drudis.2026.104685
Suzanne Tomlinson-Mathis
{"title":"A statewide multi-institutional model that de-risks academic drug discovery","authors":"Suzanne Tomlinson-Mathis","doi":"10.1016/j.drudis.2026.104685","DOIUrl":"10.1016/j.drudis.2026.104685","url":null,"abstract":"<div><div>Texas has built a coordinated, multi-institution core network that de-risks academic discoveries while reducing redundant rebuilds across institutions. Through a distributed drug R&amp;D model, autonomous cores collaborate via shared forums and referrals, making handoffs routine and providing industry-grade capabilities within academic settings. By preserving local expertise while enabling cross-core progression when data warrant, the network has delivered measurable outcomes: in a 2024 survey of ten cores, &gt;750 projects entered at least one core, &gt;70 traversed multiple cores, ∼25 patents were filed, &gt;60 startups launched and 15 programs reached the clinic; projects also attracted &gt;US$186M in non-dilutive and &gt;US$400M in dilutive capital. Together, these results demonstrate that collaboration at scale through a distributed core model can deliver meaningful translational impact.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 3","pages":"Article 104685"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809217","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
Scope of nanobodies in hepatopancreatobiliary oncology 纳米体在肝胆胰肿瘤中的应用范围。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2026-05-01 Epub Date: 2026-04-10 DOI: 10.1016/j.drudis.2026.104666
Upendra Nayek, Tusha Sharma, Vivek K. Kashyap, Shrikanth Gadad, Murali M. Yallapu, Everardo Cobos, Subhash C. Chauhan
{"title":"Scope of nanobodies in hepatopancreatobiliary oncology","authors":"Upendra Nayek,&nbsp;Tusha Sharma,&nbsp;Vivek K. Kashyap,&nbsp;Shrikanth Gadad,&nbsp;Murali M. Yallapu,&nbsp;Everardo Cobos,&nbsp;Subhash C. Chauhan","doi":"10.1016/j.drudis.2026.104666","DOIUrl":"10.1016/j.drudis.2026.104666","url":null,"abstract":"<div><div>Hepatopancreatobiliary (HPB) cancers remain among the most aggressive malignancies. Nanobodies are single-domain antibodies derived from camelid heavy-chain-only immunoglobulins. They offer distinct advantages, including small size, stability, and high antigen affinity, enabling superior tumor penetration and specificity. Emerging nanobody-drug conjugates, multispecific constructs, radiolabeled probes, and nanobody-functionalized nanoparticle platforms have shown promising preclinical outcomes in HPB cancers. Thus, this review summarizes recent advances in nanobody engineering, focusing on approaches to improve pharmacokinetics, enhance tumor penetration, enhance therapeutic performance, and modulate the tumor microenvironment. This article also addresses key challenges in the clinical translation and large-scale production of nanobodies for precise diagnosis and treatment applications in HPB oncology.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"31 3","pages":"Article 104666"},"PeriodicalIF":7.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669431","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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