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Piezo1 as a therapeutic target in kidney disease: emerging mechanistic insights and translational potential Piezo1作为肾脏疾病的治疗靶点：新兴的机制见解和转化潜力。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2026-01-01 DOI: 10.1016/j.drudis.2025.104592
Bhavana Bagdaram Choudhary, Bhupendra Puri, Anil Bhanudas Gaikwad
Piezo-type mechanosensitive ion channel component 1 (Piezo1), a mechanosensitive ion channel, has emerged as a central regulator of mechanotransduction in renal physiology and pathology. Recent findings highlight its important role in fibrosis, podocyte injury, and alterations in vascular tone by converting mechanical stimuli into calcium-dependent signaling cascades. In experimental models of acute kidney injury (AKI), chronic kidney disease (CKD), diabetic kidney disease (DKD), lupus nephritis (LN), and renal cell carcinoma (RCC). Piezo1 activation was associated with mitochondrial dysfunction, oxidative stress, and apoptosis. Conversely, pharmacological inhibition of Piezo1, particularly with the blocker GsMTxa4, alleviates fibrosis and proteinuria, establishing Piezo1 as a promising mechanosensitive therapeutic target in kidney disease.
压电型机械敏感离子通道组分1 （Piezo1）是一种机械敏感离子通道，已成为肾脏生理和病理中机械转导的中心调节器。最近的研究结果强调了它在纤维化、足细胞损伤和血管张力改变中的重要作用，通过将机械刺激转化为钙依赖的信号级联。急性肾损伤（AKI）、慢性肾病（CKD）、糖尿病肾病（DKD）、狼疮性肾炎（LN）和肾细胞癌（RCC）的实验模型。Piezo1激活与线粒体功能障碍、氧化应激和细胞凋亡有关。相反，Piezo1的药理学抑制，特别是阻滞剂GsMTxa4，减轻了纤维化和蛋白尿，使Piezo1成为肾脏疾病中有希望的机械敏感性治疗靶点。
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引用次数: 0
Plasmodium falciparum falcilysin as an emerging potential drug target for antimalarial drug discovery 恶性疟原虫毒素作为抗疟药物发现的潜在新靶点。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2026-01-01 DOI: 10.1016/j.drudis.2025.104582
Anu Dalal , Jaiveer Malik , Priyamvada Singh , Brijesh Rathi
Malaria remains a significant global health challenge, with rising drug resistance highlighting the urgent need for new therapeutic targets. Falcilysin (FLN), a conserved zinc metalloprotease essential for Plasmodium falciparum survival, has a pivotal role in hemoglobin degradation and processing transit peptides in the apicoplast. Recent studies reveal a druggable hydrophobic allosteric pocket and clarified the dynamic conformations of FLN, guiding rational inhibitor design. Multiple small-molecule classes have shown potent FLN inhibition across biochemical, cellular, and in vivo models. Key challenges include dual-organelle localization, selectivity over human homologs, and translating hits into clinical candidates. Future efforts should expand chemical diversity, explore covalent and proteolysis-targeting chimera (PROTAC) modalities, adopt multitarget strategies, and integrate cryo-electron microscopy (EM) and artificial intelligence (AI)-driven modeling for improved drug design.
疟疾仍然是一项重大的全球卫生挑战，耐药性不断上升突出表明迫切需要新的治疗靶点。恶性疟原虫溶酶（Falcilysin， FLN）是一种保守的锌金属蛋白酶，对恶性疟原虫的生存至关重要，在顶体中血红蛋白降解和转运肽的加工中起关键作用。近年来的研究揭示了一个可药物化的疏水变构口袋，阐明了FLN的动态构象，指导了抑制剂的合理设计。多种小分子类在生化、细胞和体内模型中显示出有效的FLN抑制作用。关键的挑战包括双细胞器定位，对人类同源物的选择性，以及将hit转化为临床候选物。未来的努力应扩大化学多样性，探索共价和蛋白水解靶向嵌合体（PROTAC）模式，采用多靶点策略，并整合低温电子显微镜（EM）和人工智能（AI）驱动的建模，以改进药物设计。
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引用次数: 0
Structural biology of plant-derived antibacterials: opportunities for rational lead optimization 植物源性抗菌药的结构生物学：合理导联优化的机会。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-09 DOI: 10.1016/j.drudis.2025.104580
Anupam Patra , Gajraj Singh Kushwaha
Structural biology has proven to be a pivotal tool in early-stage drug discovery, particularly in the lead optimization phase. Structure–activity relationship approaches have enabled the successful modification of plant-derived natural products into approved therapeutic agents. Despite the well-documented antibacterial potential of many phytochemicals, the number of plant-derived antibacterial drugs reaching clinical development remains limited. We highlight key case studies involving crystal structures of bacterial targets complexed with plant-derived natural products, elucidating their binding modes and mechanisms of action. We discuss the current challenges and opportunities for medicinal chemists pursuing rational lead optimization in the development of antibacterial drugs.
结构生物学已被证明是早期药物发现的关键工具，特别是在先导优化阶段。结构-活性关系方法已使植物衍生的天然产物成功修饰为批准的治疗剂。尽管许多植物化学物质具有充分的抗菌潜力，但达到临床开发的植物源性抗菌药物的数量仍然有限。我们重点介绍了涉及细菌靶点与植物来源的天然产物复杂的晶体结构的关键案例研究，阐明了它们的结合模式和作用机制。我们讨论了药物化学家在抗菌药物开发中追求合理的先导优化所面临的挑战和机遇。
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引用次数: 0
Schlafen 11 as a predictive biomarker and therapeutic target in cancer: From mechanisms to clinical application Schlafen 11作为癌症预测生物标志物和治疗靶点：从机制到临床应用
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-08 DOI: 10.1016/j.drudis.2025.104579
Shuang Xu , Kang Liu , Dan Zhang , Xiang Wang , Ying Luo , Nengming Lin
The emergence of chemotherapy resistance remains a pivotal challenge in oncology, driving the search for robust biomarkers of drug sensitivity. Schlafen 11 (SLFN11) is well established as a predictive biomarker for the response to DNA-damaging agents; however, its clinical translation is hindered by key challenges. This review systematically synthesizes current evidence on SLFN11, detailing its structure, multifaceted mechanisms, dynamic expression patterns, and epigenetic regulation. We evaluate detection methodologies, highlight the promise of dynamic monitoring via liquid biopsy, and explore rational combination therapies designed to leverage SLFN11 function. Finally, we provide a forward-looking perspective on integrating SLFN11 into biomarker-driven strategies and outline the clinical validation required to realize its full potential in precision oncology.
化疗耐药性的出现仍然是肿瘤学的关键挑战，推动了对药物敏感性生物标志物的研究。Schlafen 11 （SLFN11）已被公认为对dna损伤药物反应的预测性生物标志物；然而，其临床转化受到关键挑战的阻碍。本文系统地综合了SLFN11的现有证据，详细介绍了其结构、多方面机制、动态表达模式和表观遗传调控。我们评估了检测方法，强调了通过液体活检进行动态监测的前景，并探索了旨在利用SLFN11功能的合理联合疗法。最后，我们提供了将SLFN11整合到生物标志物驱动策略中的前瞻性观点，并概述了实现其在精确肿瘤学中的全部潜力所需的临床验证。
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引用次数: 0
Shifting global drug discovery landscape and the critical role of startups in strengthening national capabilities 全球药物研发格局的转变以及初创企业在加强国家能力方面的关键作用。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-06 DOI: 10.1016/j.drudis.2025.104576
Ryo Okuyama
This study examines the relationship between startup growth and national drug discovery capability. Analysis of the countries of origin of compounds in US Phase 3 trials compared to those of FDA-approved drugs revealed growth in Asia, particularly in China. South Korea, Australia, and Canada also showed growth, whereas Japan, Germany, and the United Kingdom showed a declining number of drugs entering Phase 3 trials. National global drug discovery share growth and the proportion of post-2000 startups contributing to Phase 3 candidates were strongly correlated, underscoring the importance of a robust startup ecosystem. Post-2000 startups produced more compounds that use new modalities. The findings highlight important implications for innovation policy to strengthen national drug discovery capability, as well as for biopharmaceutical alliance and investment strategies.
本研究探讨创业公司成长与国家药物研发能力的关系。对美国三期试验中化合物的原产国与fda批准药物的原产国进行的分析显示，亚洲的增长，尤其是中国。韩国、澳大利亚和加拿大也出现了增长，而日本、德国和英国进入3期试验的药物数量则出现了下降。国家全球药物研发份额的增长与00后创业公司为3期候选药物做出贡献的比例密切相关，强调了强大的创业生态系统的重要性。00后创业公司生产了更多使用新模式的化合物。研究结果对加强国家药物研发能力的创新政策以及生物制药联盟和投资战略具有重要意义。
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引用次数: 0
Computational approaches enhance the design of molecular glue degraders for undruggable proteins 计算方法增强了不可药物蛋白质分子胶降解剂的设计。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-06 DOI: 10.1016/j.drudis.2025.104577
Sirishantha G.M.A. Deshani , Gunarathna R.D.S. Madushani , Karunaratne Veranja , Kumar Vinit , Hao Ge-Fei
Most proteins remain ‘undruggable’ by traditional approaches, which are unable to engage targets because of a lack of well-defined binding pockets, causing a bottleneck in drug discovery. Molecular glue degraders (MGDs) have emerged as a promising therapeutic strategy for targeting previously undruggable proteins. However, despite their potential, only a few MGDs have received FDA approval, highlighting gaps in off-target effects, drug resistance, and substrate availability. Here, we discuss recent MGD breakthroughs driven by the integration of structure-based computational approaches and AI platforms, which have accelerated MGD design with improved accuracy. Looking ahead, advances in quantum computing and AI-based generative models might open pathways to innovative treatments, targeting diseases once considered incurable.
大多数蛋白质通过传统方法仍然是“不可药物的”，由于缺乏明确定义的结合袋，传统方法无法接触靶标，从而导致药物发现的瓶颈。分子胶降解剂（MGDs）已成为一种有前途的治疗策略，针对以前不可药物的蛋白质。然而，尽管具有潜力，只有少数MGDs获得了FDA的批准，这突出了脱靶效应、耐药和底物可用性方面的差距。在这里，我们讨论了最近由基于结构的计算方法和人工智能平台的集成驱动的MGD突破，这些突破加速了MGD设计，提高了精度。展望未来，量子计算和基于人工智能的生成模型的进步可能会为创新治疗开辟道路，针对曾经被认为无法治愈的疾病。
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引用次数: 0
The role of seaweed-derived natural components in obesity: A systematic review 海藻衍生的天然成分在肥胖中的作用：系统综述。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-05 DOI: 10.1016/j.drudis.2025.104575
Jiao Tan , K.K. Asanka Sanjeewa , Ginnae Ahn , You-Jin Jeon , Lei Wang
Obesity results from an imbalance between energy intake and expenditure, with over-processed foods and sedentary lifestyles being key contributors to the growing global obesity epidemic. This condition has numerous complications like hypertension, diabetes, fatty liver, and reproductive disorders, significantly endangering human health. Preventing and addressing obesity-related health issues have become a primary focus of health research. As promising anti-obesity drug candidates, seaweeds have attracted increasing researcher interest because of their abundant bioactive secondary metabolites with disease-treating properties. Specifically, a number of studies have confirmed the anti-obesity potential of bioactive secondary metabolites derived from seaweeds. In this review, the authors summarize the models of obesity and the potential of seaweed-derived bioactive components to treat obesity-related disorders.
肥胖是由能量摄入和消耗之间的不平衡造成的，过度加工的食品和久坐不动的生活方式是全球肥胖流行病日益严重的主要原因。这种疾病有许多并发症，如高血压、糖尿病、脂肪肝和生殖障碍，严重危害人类健康。预防和解决肥胖相关的健康问题已成为健康研究的主要焦点。海藻作为一种很有前景的抗肥胖药物，由于其丰富的生物活性次生代谢物具有治疗疾病的特性而引起了越来越多研究者的兴趣。具体来说，许多研究已经证实了来自海藻的生物活性次生代谢物具有抗肥胖的潜力。在这篇综述中，作者总结了肥胖的模型和海藻衍生的生物活性成分治疗肥胖相关疾病的潜力。
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引用次数: 0
Linear triazenes: Versatile scaffolds for chemical biology and drug design 线性三氮杂烯：化学生物学和药物设计的多功能支架。
IF 7.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-04 DOI: 10.1016/j.drudis.2025.104574
Ahammed Ameen Thottasseri , Anju Agnes Tom , Deepthi Ramesh , Ramkishore Matsa , Tharanikkarasu Kannan
Analyzing the advances in and emergence of novel triazenes is pivotal in medicinal chemistry. Triazenes exhibit biological activity through alkylation, redox processes, or interactions with biomolecules, producing synergistic effects enabling the synthesis of derivatives with tailored pharmacokinetic profiles and enhanced activities. Although cyclic triazenes are well studied, research on linear triazenes has largely focused on their anticancer potential, leaving other therapeutic areas less explored. Given the need for chemotypes with modular synthesis and favorable pharmacology, linear triazenes warrant renewed attention. This review provides a comprehensive overview of the chemistry, biological activity, and structure–activity relationships of linear triazenes, highlighting their emerging roles in targeted therapies, fragment-based design, and bifunctional modalities, as reported since 2000.
分析新型三氮杂烯类化合物的研究进展和出现是药物化学研究的关键。三氮杂烯通过烷基化、氧化还原过程或与生物分子的相互作用表现出生物活性，产生协同效应，从而合成具有定制药代动力学特征和增强活性的衍生物。尽管环三氮烯已经得到了很好的研究，但对线性三氮烯的研究主要集中在它们的抗癌潜力上，而对其他治疗领域的探索较少。考虑到需要模块化合成的化学型和有利的药理学，线性三氮杂烯值得重新关注。本文综述了线性三氮杂烯的化学、生物活性和构效关系，重点介绍了自2000年以来它们在靶向治疗、基于片段的设计和双功能模式中的新兴作用。
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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 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-04 DOI: 10.1016/j.drudis.2025.104564
Charles H. Jones
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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 Q1 PHARMACOLOGY & PHARMACY
Drug Discovery Today
Pub Date : 2025-12-04 DOI: 10.1016/j.drudis.2025.104573
Tam Nguyen, Elena Koustova
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.
目标产品概要（TPPs）通过定义针对特定疾病或需求的所需特性来指导医疗产品开发。通过指定安全性、有效性、可用性、可及性和差异性，TPPs有助于优先分配资源，尽早发现挑战，并降低故障风险。虽然在药物开发中很常见，但TPPs很少应用于物质使用障碍（sud）。本文展示了SUD TPP应如何平衡监管可行性、临床相关性和商业可行性。我们提供了一个关于阿片类药物使用障碍药物的TPP例子，以测试现有疗法的差异化和市场假设。tpp将注意力集中在机械新颖性之外，阐明了独特的产品属性。深思熟虑的TPP设计增加了产品安全、有效、可获得、可报销和公平分配的机会。
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引用次数: 0
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