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Beyond purinergic signaling: Dual ligand approaches to multitarget drug discovery 超越嘌呤能信号：多靶点药物发现的双配体方法。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-15 DOI: 10.1016/j.drudis.2025.104457
Beatrice Francucci, Aleksei Smirnov, Andrea Spinaci, Michela Buccioni, Gabriella Marucci
{"title":"Beyond purinergic signaling: Dual ligand approaches to multitarget drug discovery","authors":"Beatrice Francucci,&nbsp;Aleksei Smirnov,&nbsp;Andrea Spinaci,&nbsp;Michela Buccioni,&nbsp;Gabriella Marucci","doi":"10.1016/j.drudis.2025.104457","DOIUrl":"10.1016/j.drudis.2025.104457","url":null,"abstract":"<div><div>Purinergic receptors represent an attractive target for treating numerous multifactorial diseases currently considered incurable. Multitargeted agents binding purinergic receptors show considerable promise in preclinical studies in several diseases. Most of the multifactorial pathologies for which no therapy is currently known represent the greatest challenge for the pharmaceutical community. Molecules directed simultaneously toward multiple targets could counteract the redundancy phenomena typical of biological systems and avoid the side effects associated with drug cocktails. This review is intended to provide a summary of the most significant dual ligands able to interact with purinergic receptors and other G-protein-coupled receptors or enzymes.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 10","pages":"Article 104457"},"PeriodicalIF":7.5,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870705","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
Covalent ligand efficiency 共价配体效率。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-13 DOI: 10.1016/j.drudis.2025.104454
György G. Ferenczy , György M. Keserű
{"title":"Covalent ligand efficiency","authors":"György G. Ferenczy ,&nbsp;György M. Keserű","doi":"10.1016/j.drudis.2025.104454","DOIUrl":"10.1016/j.drudis.2025.104454","url":null,"abstract":"<div><div>Ligand efficiency (<em>LE</em>) expresses the binding affinity of the ligand to its protein target normalized by ligand size. Although the concept is well established for noncovalent ligands, its extension to irreversible covalent ligands is not straightforward. Here, we analyze noncovalent and covalent contributions to the affinity and propose a new metric, named covalent ligand efficiency (<em>CLE</em>), which comprises affinity and reactivity information. <em>CLE</em> is originally defined for cysteine targeting ligands and its formula includes <em>IC</em><sub><em>50</em></sub> against the target protein and reactivity rate constant toward glutathione (GSH). <em>CLE</em> and <em>LE</em> were comparatively analyzed for over 6500 cysteine-targeting covalent ligands. <em>CLE</em> can be extended to ligands targeting noncysteine residues by adjusting the reactivity contribution to the corresponding surrogate.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104454"},"PeriodicalIF":7.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858739","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
Adipose tissue NLRP3 inflammasome: a therapeutic target in obesity and type 2 diabetes mellitus 脂肪组织NLRP3炎性体：肥胖和2型糖尿病的治疗靶点
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-13 DOI: 10.1016/j.drudis.2025.104456
Ngozi Francisca Nnolum-Orji, Pradeep Kumar, Lindokuhle Malibongwe Ngema, Yahya Essop Choonara
{"title":"Adipose tissue NLRP3 inflammasome: a therapeutic target in obesity and type 2 diabetes mellitus","authors":"Ngozi Francisca Nnolum-Orji,&nbsp;Pradeep Kumar,&nbsp;Lindokuhle Malibongwe Ngema,&nbsp;Yahya Essop Choonara","doi":"10.1016/j.drudis.2025.104456","DOIUrl":"10.1016/j.drudis.2025.104456","url":null,"abstract":"<div><div>Adipose tissue has been identified as a crucial player in the release of proinflammatory mediators, which can result in a chronic inflammatory state, predisposing individuals to obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM). A major approach in tackling these diseases involves targeting molecular sensors that can respond to nutritional cues and metabolic status that trigger the early phases of inflammatory cascades. Among these sensors is the nucleotide oligomerization domain (NOD)-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Therapeutic strategies targeting the adipose tissue NLRP3 inflammasome show potential for the management of obesity and T2DM. In this review, we provide insights into this potential, the current therapeutic strategies, and recent clinical advances.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104456"},"PeriodicalIF":7.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858737","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
Galectins in inflammatory skin diseases: current roles and future directions 凝集素在炎症性皮肤病中的作用及未来发展方向。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-13 DOI: 10.1016/j.drudis.2025.104455
Mab P. Corrêa , Rebeca D. Correia-Silva , Diego D. Santos , Karin V. Greco , Cristiane D. Gil
{"title":"Galectins in inflammatory skin diseases: current roles and future directions","authors":"Mab P. Corrêa ,&nbsp;Rebeca D. Correia-Silva ,&nbsp;Diego D. Santos ,&nbsp;Karin V. Greco ,&nbsp;Cristiane D. Gil","doi":"10.1016/j.drudis.2025.104455","DOIUrl":"10.1016/j.drudis.2025.104455","url":null,"abstract":"<div><div>Galectins (LGALS) are β-galactoside-binding lectins involved in immune regulation, epithelial integrity, and tissue remodeling. In the skin, they exhibit cell type-specific expression across keratinocytes, fibroblasts, and immune cells, shaping inflammatory signaling and barrier homeostasis. In this review, we examine LGALS expression and function in inflammatory skin diseases, with a focus on atopic dermatitis (AD) and psoriasis (Pso). In AD, LGALS1, -3, -7, -9, and -10 are linked to Th2/Th22 responses and barrier dysfunction. In Pso, reduced LGALS1, -3, and -7 contrast with the proproliferative effects of LGAS-8 and immunomodulatory role of LGALS9. These findings highlight the diagnostic and therapeutic potential of LGALS, supporting their relevance in precision medicine and targeted approaches for chronic skin inflammation.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104455"},"PeriodicalIF":7.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858741","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
Commercialization of cell and gene therapy in Canada: Current landscape, challenges and opportunities 加拿大细胞和基因治疗的商业化：现状、挑战和机遇。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-13 DOI: 10.1016/j.drudis.2025.104453
Logan S. Germain , Louise M. Winn
{"title":"Commercialization of cell and gene therapy in Canada: Current landscape, challenges and opportunities","authors":"Logan S. Germain ,&nbsp;Louise M. Winn","doi":"10.1016/j.drudis.2025.104453","DOIUrl":"10.1016/j.drudis.2025.104453","url":null,"abstract":"<div><div>Cell and gene therapies (CGTs) offer transformative treatments for certain genetic diseases and cancers, with a growing number of global approvals. Yet Canadian commercialization lags behind the USA and Europe. This review identifies key barriers and proposes policy solutions informed by international examples. A policy-oriented environmental scan was conducted using regulatory documents, peer-reviewed literature, government reports, and industry publications. Barriers and solutions are organized into four domains: regulation, manufacturing, pricing and reimbursement, and access and equity. Despite recent investment downturns in this therapeutic area, Canada’s approval of its first clustered regularly interspaced short palindromic repeats (CRISPR)-based therapy and chimeric antigen receptor (CAR) T-cell expansion suggest future growth. Strategic reforms could improve domestic CGT innovation, affordability, and equitable access.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 10","pages":"Article 104453"},"PeriodicalIF":7.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858738","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
Discovery of novel anti-fibrotics through phenotypic screening 通过表型筛选发现新型抗纤维化药物。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-13 DOI: 10.1016/j.drudis.2025.104450
Alice R. Lapthorn, Sophie L. Harding-Fox, Kieran M. Feltham, Marcus M. Ilg, Selim Cellek
{"title":"Discovery of novel anti-fibrotics through phenotypic screening","authors":"Alice R. Lapthorn,&nbsp;Sophie L. Harding-Fox,&nbsp;Kieran M. Feltham,&nbsp;Marcus M. Ilg,&nbsp;Selim Cellek","doi":"10.1016/j.drudis.2025.104450","DOIUrl":"10.1016/j.drudis.2025.104450","url":null,"abstract":"<div><div>Fibrosis is defined as the excessive accumulation of extracellular matrix (ECM) components following injury, affecting any organ in the human body. Fibrotic diseases of the vital organs (e.g. lung, heart, kidney, and liver) can be chronic, progressive, irreversible, and fatal. Although fibrotic diseases account for 45% of the mortality in the Western world, the available treatment options are limited in number, efficacy, and safety. There is a lack of progress in the development of novel anti-fibrotics, which has been attributed to a reliance on target-based screening. Phenotypic screening has been shown to be more successful in identifying first-in-class drugs compared with the target-based approach. Here we critically review the current landscape of phenotypic screening campaigns in fibrosis, evaluate their success in identifying translatable lead compounds, and highlight methodological pitfalls.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104450"},"PeriodicalIF":7.5,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858740","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
Future potential therapeutics to treat MASH 未来治疗MASH的潜在疗法。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-11 DOI: 10.1016/j.drudis.2025.104451
Shriram Mahajan, Navya Malladi, Sanjay K. Banerjee
{"title":"Future potential therapeutics to treat MASH","authors":"Shriram Mahajan,&nbsp;Navya Malladi,&nbsp;Sanjay K. Banerjee","doi":"10.1016/j.drudis.2025.104451","DOIUrl":"10.1016/j.drudis.2025.104451","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of Metabolic-associated steatotic liver disease (MASLD), poses a significant global health challenge due to its association with obesity, type 2 diabetes, and cardiovascular complications. Despite its rising prevalence, effective therapies remain limited. This review highlights emerging therapeutic strategies that target key pathways involved in MASH pathogenesis, including THR-β, FXR, PPAR, GLP-1RA, FGF21, and SGLT2. In addition, novel approaches such as gene therapy (siRNA), probiotics, fecal microbiota transplantation, and stem cell therapy show promise for the treatment of MASH. Ongoing clinical trials and mechanistic insights into fibrosis, inflammation, and lipid metabolism provide hope for tailored, multi-targeted treatments. Future efforts must address safety, long-term efficacy, and non-invasive diagnostics to advance the management of MASH.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104451"},"PeriodicalIF":7.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843957","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
New approach methodologies (NAMs) for drug-induced liver injury (DILI): Where are we now? 药物性肝损伤（DILI）的新方法方法（NAMs）：我们现在在哪里？
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-11 DOI: 10.1016/j.drudis.2025.104452
Shivangi Shrimali, Minjun Chen, Dongying Li, Weida Tong
{"title":"New approach methodologies (NAMs) for drug-induced liver injury (DILI): Where are we now?","authors":"Shivangi Shrimali,&nbsp;Minjun Chen,&nbsp;Dongying Li,&nbsp;Weida Tong","doi":"10.1016/j.drudis.2025.104452","DOIUrl":"10.1016/j.drudis.2025.104452","url":null,"abstract":"<div><div>The FDA’s ‘Roadmap to Reducing Animal Testing in Preclinical Safety Studies’ supports the regulatory advancement of new approach methodologies (NAMs). Focusing on overlapping drugs, this review compared the performance of <em>in vitro</em> NAMs, animal studies, and microphysiological systems (MPS) in predicting drug-induced liver injury (DILI). We observed considerable variability among <em>in vitro</em> NAMs and their potential advantages over animal models. Moreover, limited MPS data hindered meaningful comparison. To enable objective and systematic assessment of NAMs, we propose DILIference, a curated reference drug list compiled from the literature to guide the development and benchmarking of DILI-predictive NAMs.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104452"},"PeriodicalIF":7.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843958","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
Role of P2Y6R in cancer and its antagonists P2Y6R在癌症及其拮抗剂中的作用。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-08 DOI: 10.1016/j.drudis.2025.104449
Xin Wang , Jiliang Zhang , Yongtao Duan , Chuanjun Song
{"title":"Role of P2Y6R in cancer and its antagonists","authors":"Xin Wang ,&nbsp;Jiliang Zhang ,&nbsp;Yongtao Duan ,&nbsp;Chuanjun Song","doi":"10.1016/j.drudis.2025.104449","DOIUrl":"10.1016/j.drudis.2025.104449","url":null,"abstract":"<div><div>P2Y<sub>6</sub>R, a target that has garnered extensive research attention in recent years, has been implicated in a diverse range of diseases. Specifically, abnormally high expression levels of P2Y<sub>6</sub>R have been identified in various tumor tissues and cells and are closely associated with the degree of malignancy and metastasis of the tumor. Antagonists against P2Y<sub>6</sub>R have been shown to effectively block signaling pathways that promote tumor growth, thereby inhibiting cancer cell proliferation, migration, and invasion. These findings suggest that targeting P2Y<sub>6</sub>R is a promising strategy for cancer treatment. This review summarizes the role of P2Y<sub>6</sub>R in cancer, the anticancer mechanisms, and research progress related to the antagonists.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104449"},"PeriodicalIF":7.5,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815426","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
Revolutionizing drug discovery: Integrating artificial intelligence with quantitative systems pharmacology 革命性的药物发现：整合人工智能与定量系统药理学。
IF 7.5 2区 医学
Drug Discovery Today Pub Date : 2025-08-06 DOI: 10.1016/j.drudis.2025.104448
Igor Goryanin , Irina Goryanin , Oleg Demin
{"title":"Revolutionizing drug discovery: Integrating artificial intelligence with quantitative systems pharmacology","authors":"Igor Goryanin ,&nbsp;Irina Goryanin ,&nbsp;Oleg Demin","doi":"10.1016/j.drudis.2025.104448","DOIUrl":"10.1016/j.drudis.2025.104448","url":null,"abstract":"<div><div>Quantitative systems pharmacology (QSP) provides a mechanistic framework for integrating diverse biological, physiological, and pharmacological data to predict drug interactions and clinical outcomes. Recent advances in artificial intelligence (AI) might transform QSP by enhancing model generation, parameter estimation, and predictive capabilities. AI-driven databases and cloud-based platforms might support QSP model development and facilitate QSP as a service (QSPaaS). However, challenges such as computational complexity, high dimensionality, explainability, data integration, and regulatory acceptance persist. This review critically evaluates the integration of AI within QSP, highlighting novel methodologies like surrogate modeling, virtual patient generation, and digital twin technologies. It also discusses current limitations and outlines strategies for future integration to enhance precision medicine, regulatory acceptability, and mechanistic interpretability in drug discovery and development.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"30 9","pages":"Article 104448"},"PeriodicalIF":7.5,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144797769","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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