Medicinal Research Reviews最新文献_第7页

Smart Integration of Structural Biology and Medicinal Chemistry to Unlock Target-Driven Drug Discovery 结构生物学和药物化学的智能集成解锁靶标驱动的药物发现。

IF 11.6 1区医学

Medicinal Research Reviews Pub Date : 2026-06-01 Epub Date: 2026-03-16 DOI: 10.1002/med.70038

Matteo Rossi Sebastiano, Giulia Apprato, Serena Francisco, Giuseppe Ermondi, Giulia Caron

{"title":"Smart Integration of Structural Biology and Medicinal Chemistry to Unlock Target-Driven Drug Discovery","authors":"Matteo Rossi Sebastiano, Giulia Apprato, Serena Francisco, Giuseppe Ermondi, Giulia Caron","doi":"10.1002/med.70038","DOIUrl":"10.1002/med.70038","url":null,"abstract":"<p>To enhance drug discovery efforts, medicinal chemists should evaluate, filter, and utilize relevant structural information about target proteins. Acquiring and interpreting protein structures is crucial for elucidating ligand-receptor interactions and addressing ADME-related considerations, making it an essential aspect of medicinal chemistry. Proteins exhibit diverse structural organizations, and their conformational variability poses challenges for drug design. Here we draw from our own experience how advances in structural biology have improved medicinal chemists’ access to 3D protein structures and dynamics, while stressing the need for model validation and refinement. To highlight the influence of structural biology on drug discovery, we present case studies. Structural insights into P-glycoprotein have been crucial in addressing multidrug resistance, while the analysis of the oncoprotein β-catenin provides valuable guidance for developing future therapeutic strategies based on innovative technology like targeted protein degradation. Finally, we report about multimeric complexes of proteins (Alsin and AP-4) involved in rare HSPs and the contribution of protein–protein interaction analyses to discover mutation-specific drugs.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"46 4","pages":"921-944"},"PeriodicalIF":11.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/med.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advances in SIRT2-Targeted Therapeutics: Structural Insights, Chemical Strategies, and Degrader Technologies sirt2靶向治疗的进展：结构见解、化学策略和降解技术。

IF 11.6 1区医学

Medicinal Research Reviews Pub Date : 2026-06-01 Epub Date: 2026-05-05 DOI: 10.1002/med.70054

Ahmed A. Al-Karmalawy, Wolfgang Sippl, Abdullah Al-Dakhil, Tarek A. Yousef, Arwa Omar Al Khatib, Samia S. Hawas

{"title":"Advances in SIRT2-Targeted Therapeutics: Structural Insights, Chemical Strategies, and Degrader Technologies","authors":"Ahmed A. Al-Karmalawy, Wolfgang Sippl, Abdullah Al-Dakhil, Tarek A. Yousef, Arwa Omar Al Khatib, Samia S. Hawas","doi":"10.1002/med.70054","DOIUrl":"10.1002/med.70054","url":null,"abstract":"<div>\u0000 \u0000 <p>Sirtuin 2 (SIRT2) is an NAD⁺-dependent lysine deacylase that is a member of the sirtuin enzyme family and plays essential roles in cytoskeletal regulation, chromatin remodeling, metabolic control, inflammation, neurodegeneration, and cancer progression. Its diverse biological functions have positioned SIRT2 as a compelling but challenging therapeutic target. This review provides an integrated overview of recent advances in SIRT2 structural biology, emphasizing the catalytic core, substrate-binding channel, and the inducible selectivity pocket that enables isoform discrimination. We summarize the medicinal chemistry landscape of classical SIRT2 inhibitors, highlighting major scaffolds and determinants of potency and selectivity. Emerging strategies based on targeted protein degradation—including SirReal-derived PROTACs, hydrophobic-tag degraders, and non-CRBN E3 ligase systems—are discussed in comparison with traditional occupancy-driven inhibition, underscoring the advantages of event-driven degradation for eliminating both catalytic and non-catalytic SIRT2 functions. Drug repurposing efforts and computational screening approaches further expand the repertoire of potential SIRT2 modulators. Finally, we outline current challenges and future directions, including the need for improved selectivity, better pharmacokinetic profiles, deeper mechanistic understanding, and development of chemical probes for underexplored sirtuin isoforms. Together, these advances highlight the rapidly evolving landscape of SIRT2-targeted therapeutics and their emerging potential in oncology, neurodegeneration, and metabolic disease.</p>\u0000 </div>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"46 4","pages":"1230-1250"},"PeriodicalIF":11.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Tirzepatide in Metabolic Diseases: Clinical Efficacy and Safety Beyond Diabetes and Obesity 替西肽治疗代谢性疾病：糖尿病和肥胖症以外的临床疗效和安全性。

IF 11.6 1区医学

Medicinal Research Reviews Pub Date : 2026-06-01 Epub Date: 2026-04-01 DOI: 10.1002/med.70049

Shixuan Dong, Ying Xu, Ran Gan, Ailin Zhang, Jinhan He, Qin Tang

{"title":"Tirzepatide in Metabolic Diseases: Clinical Efficacy and Safety Beyond Diabetes and Obesity","authors":"Shixuan Dong, Ying Xu, Ran Gan, Ailin Zhang, Jinhan He, Qin Tang","doi":"10.1002/med.70049","DOIUrl":"10.1002/med.70049","url":null,"abstract":"<div>\u0000 \u0000 <p>Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has attracted substantial attention for its exceptional efficacy in managing type 2 diabetes and obesity. Emerging evidence suggests that tirzepatide may also exert broad therapeutic benefits in cardiovascular diseases, metabolic dysfunction-associated steatotic liver disease, and chronic kidney disease. However, its potential clinical risks are increasingly being recognized. This review begins by outlining the structural and pharmacological advantages of tirzepatide. We then comprehensively evaluate recent clinical evidence, including randomized controlled trials and real-world studies, based on a comprehensive literature search, to analyze its efficacy and safety for metabolic disorders. Tirzepatide exhibits considerable promise in treating multiple metabolic diseases; however, its therapeutic benefits must be carefully weighed against potential risks. Conclusions on cardiorenal benefits are supported by high-level outcome trials, while the evidence for hepatic, renal and musculoskeletal effects is exploratory or preliminary. Further large-scale, long-term studies remain essential to fully elucidate its mechanisms of action and overall clinical impact, given the current safety signals and other evidence are largely based on case reports, post hoc analyses, and non-prespecified endpoints. Continued pharmacovigilance is also crucial to identify and mitigate potential adverse drug reactions in diverse patient populations, especially for rare but serious events identified through spontaneous reporting systems.</p></div>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"46 4","pages":"1026-1041"},"PeriodicalIF":11.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147589073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Multi-Targeting Ligands as Prospective Therapeutics for Alzheimer's Disease, a Prevalent Neurodegenerative Disorder: Mechanistic Insights, Emerging Targets and Drug Discovery Campaigns 多靶向配体作为阿尔茨海默病（一种普遍的神经退行性疾病）的前瞻性治疗方法：机制见解、新靶点和药物发现活动。

IF 11.6 1区医学

Medicinal Research Reviews Pub Date : 2026-06-01 Epub Date: 2026-04-19 DOI: 10.1002/med.70047

Amandeep Thakur, Mandeep Rana, Sakshi Vanjani, Kei-Chi Liou, Rajeev Taliyan, Kunal Nepali, Chih-Hao Yang

{"title":"Multi-Targeting Ligands as Prospective Therapeutics for Alzheimer's Disease, a Prevalent Neurodegenerative Disorder: Mechanistic Insights, Emerging Targets and Drug Discovery Campaigns","authors":"Amandeep Thakur, Mandeep Rana, Sakshi Vanjani, Kei-Chi Liou, Rajeev Taliyan, Kunal Nepali, Chih-Hao Yang","doi":"10.1002/med.70047","DOIUrl":"10.1002/med.70047","url":null,"abstract":"<p>Alzheimer's disease (AD) is a debilitating neurodegenerative condition characterized by progressive cognitive impairment, memory deterioration, and neuronal dysfunction. Its complex pathophysiology involves multiple interlinked processes, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, synaptic dysfunction, and cholinergic deficits. Current FDA-approved therapies provide only symptomatic relief and fail to halt disease progression, highlighting the urgent need for more effective treatment strategies. This review provides a comprehensive overview of the pathological mechanisms underlying AD and the emerging therapeutic targets for the design of tractable anti-AD scaffolds, namely, acetylcholinesterase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), glycogen synthase kinase-3β (GSK3β), dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), histone deacetylases (HDACs), and soluble epoxide hydrolase (sEH). Emphasis is placed on the paradigm shift from single-target therapies to multitarget-directed ligands (MTDLs), which are increasingly recognized as promising tools to tackle AD's multifactorial pathology. We also discuss recent advances in medicinal chemistry and structure-guided drug discovery campaigns aimed at developing pharmacologically optimized, BBB-penetrant MTDLs. By consolidating mechanistic insights with therapeutic innovation, this review aims to facilitate the development of next-generation therapeutics with enhanced efficacy and disease-modifying potential in AD.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"46 4","pages":"1173-1229"},"PeriodicalIF":11.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/med.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147715343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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A Comprehensive Review of Marketed KRAS Inhibitors and Degraders: Challenges and Opportunities 市场上KRAS抑制剂和降解剂的综合综述：挑战和机遇。

IF 11.6 1区医学

Medicinal Research Reviews Pub Date : 2026-06-01 Epub Date: 2026-02-09 DOI: 10.1002/med.70035

Yi-Xin Xu, Yi-Ru Bai, Ruifang Li, Yi-Ming Peng, Ting-Ting Liu, Xin Yang, Ke-Tong Chen, Zhi-Peng Jin, Hong-Min Liu, Shuo Yuan

引用次数: 0

Beyond Antiviral Therapy: Untapped Potential of HIV & HCV Protease Inhibitors 超越抗病毒治疗：HIV和HCV蛋白酶抑制剂尚未开发的潜力。

IF 11.6 1区医学

Medicinal Research Reviews Pub Date : 2026-06-01 Epub Date: 2026-04-02 DOI: 10.1002/med.70040

Dmitrii A. Iuzabchuk, Anastasia A. Andrianova, Ilia V. Yampolsky, Zinaida M. Kaskova, Ivan V. Smirnov

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Recent Advances of Non-Nucleoside Polymerase Inhibitors With Broad-Spectrum Antiviral Activities 具有广谱抗病毒活性的非核苷聚合酶抑制剂的研究进展。

IF 11.6 1区医学

Medicinal Research Reviews Pub Date : 2026-06-01 Epub Date: 2026-03-22 DOI: 10.1002/med.70041

Sining Tao, Zhenzhen Zhou, Xin Li, Xian-Wei Wang, Xinyong Liu, Dongwei Kang

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In Memoriam: Professor Minyong Li (1976–2025) 纪念：李敏勇教授（1976-2025）

IF 11.6 1区医学

Medicinal Research Reviews Pub Date : 2026-06-01 Epub Date: 2026-01-11 DOI: 10.1002/med.70032

Laura Mercolini

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Accelerating Small Molecule Ferroptosis Regulator Development With Advances in Biological Functions 随着生物功能的进展，加速小分子铁下垂调节剂的开发。

IF 11.6 1区医学

Medicinal Research Reviews Pub Date : 2026-06-01 Epub Date: 2026-02-23 DOI: 10.1002/med.70034

Linyue Bai, Liang Shen, Qianqian Zhang, Zhuang Hu, Yanjun Tang, Mengjie Fu, Yange Fan, Huifeng Wang, Hong-Min Liu, Xing-Jie Dai, Siqi Feng

{"title":"Accelerating Small Molecule Ferroptosis Regulator Development With Advances in Biological Functions","authors":"Linyue Bai, Liang Shen, Qianqian Zhang, Zhuang Hu, Yanjun Tang, Mengjie Fu, Yange Fan, Huifeng Wang, Hong-Min Liu, Xing-Jie Dai, Siqi Feng","doi":"10.1002/med.70034","DOIUrl":"10.1002/med.70034","url":null,"abstract":"<div>\u0000 \u0000 <p>Ferroptosis is an iron-dependent cell death characterized by the disorder of iron homeostasis and the accumulation of lipid peroxidation, which trigger a cascade of events resulting in cell death. This process has a dual regulatory effect in the evolution of diseases, which can not only attenuate the progress of diseases, but also become a promoting force to accelerate pathological alterations, and widely participate in the occurrence and development of multiple diseases. In recent years, there has been a growing body of research identifying regulators—both inducers and inhibitors—that target the mechanisms of ferroptosis, particularly in the field of anti-tumor drug research. This review systematically elucidates the regulatory mechanisms underlying ferroptosis (e.g., iron metabolism, lipid peroxidation, system Xc<sup>−</sup>/GSH/GPX4 axis) and examines the role of ferroptosis in the pathogenesis of various diseases, such as cancer, neurodegenerative diseases, liver and kidney diseases, and cardiovascular diseases. Additionally, we discussed the therapeutic applications of novel inducers and inhibitors of ferroptosis in recent years, offering critical insights and directions for further researching on the mechanism of ferroptosis and targeted drugs for ferroptosis-related diseases.</p></div>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"46 4","pages":"853-895"},"PeriodicalIF":11.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Unravelling Structure-Based Molecular Activation and Antagonism of Protease-Activated Receptors for Drug Design 揭示基于结构的蛋白酶激活受体的分子激活和拮抗作用，用于药物设计。

IF 11.6 1区医学

Medicinal Research Reviews Pub Date : 2026-06-01 Epub Date: 2026-04-02 DOI: 10.1002/med.70048

Zhikang Xu, Rui Li, Jian Zhang

引用次数: 0