Annual review of pharmacology and toxicology最新文献_第2页

Emerging Roles of Mass Spectrometry-Based Proteomics in Drug Discovery. 基于质谱的蛋白质组学在药物发现中的新作用。

IF 19 1区医学

Annual review of pharmacology and toxicology Pub Date : 2026-10-01 DOI: 10.1146/annurev-pharmtox-060325-040513

Ka Yang, Weiping Tang, Taosheng Chen, Junmin Peng

{"title":"Emerging Roles of Mass Spectrometry-Based Proteomics in Drug Discovery.","authors":"Ka Yang, Weiping Tang, Taosheng Chen, Junmin Peng","doi":"10.1146/annurev-pharmtox-060325-040513","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060325-040513","url":null,"abstract":"Mass spectrometry (MS)-based proteomics has emerged as a versatile platform in modern drug discovery, enabling system-wide interrogation of protein abundance, posttranslational modifications (PTMs), turnover, structural stability, and interactions with small molecules in native biological contexts. In this review, we introduce recent advances in MS and summarize how scalable, high-throughput technologies support target identification and mechanism-of-action studies. We discuss global profiling of the proteome and PTMs under drug perturbation, as well as proteome-wide stability assays such as thermal proteome profiling and limited proteolysis-MS. We further discuss activity-based protein profiling, fully functionalized and photoaffinity probes, and affinity-matrix approaches that expand covalent and noncovalent ligand discovery. Finally, we highlight multiple proteomics-driven strategies in targeted protein degradation. Together, these integrated MS-based approaches in drug discovery, often termed chemoproteomics, provide a coherent framework for linking chemical perturbations to functional proteome remodeling, expanding the druggable proteome and accelerating therapeutic development.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103125","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

Molecular Pharmacology of Dopamine Receptors: Structure, Function, and Therapeutic Implications. 多巴胺受体的分子药理学：结构、功能和治疗意义。

IF 19 1区医学

Annual review of pharmacology and toxicology Pub Date : 2026-10-01 DOI: 10.1146/annurev-pharmtox-060425-070659

Youwen Zhuang, H Eric Xu

{"title":"Molecular Pharmacology of Dopamine Receptors: Structure, Function, and Therapeutic Implications.","authors":"Youwen Zhuang, H Eric Xu","doi":"10.1146/annurev-pharmtox-060425-070659","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060425-070659","url":null,"abstract":"Dopamine receptors (DRs) mediate central and peripheral dopaminergic signaling and remain major therapeutic targets in movement disorders, psychiatric disease, and endocrine dysfunction. Despite decades of clinical use, existing DR-directed therapies still suffer from limited subtype selectivity, pathway-nonspecific engagement, and substantial adverse effects, reflecting an incomplete molecular understanding of receptor function. In this review, we examine recent advances in DR molecular pharmacology, focusing on how structural, pharmacological, and computational studies have clarified receptor activation, inverse agonism, transducer coupling, signaling bias, allosteric modulation, and ligand selectivity through analyses of inactive and active receptor states, including family-wide receptor-G protein complexes. We discuss how ligand-specific receptor conformations, transducer interactions, and membrane environment shape signaling output, help explain the diverse actions of dopaminergic ligands, and distinguish the activation trajectories of D1-like and D2-like receptors. We also consider how these advances, including insights into allosteric sites, transducer selectivity, and AI-assisted discovery, inform the development of more selective and precise dopaminergic therapies. Together, these developments are shifting the field from descriptive receptor pharmacology toward a mechanistic and structure-guided framework for therapeutic discovery.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103207","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

Novel Targets and Treatments for Neurodegenerative Diseases Revealed by Drosophila. 果蝇揭示神经退行性疾病的新靶点和治疗方法。

IF 19 1区医学

Annual review of pharmacology and toxicology Pub Date : 2026-09-25 DOI: 10.1146/annurev-pharmtox-060325-064705

Pablo Reina-Gonzalez, Aiesha Anchan, Jennifer Bekos, Abdulla Abu-Salah, Souvarish Sarkar

引用次数: 0

Use of High-Resolution Mass Spectrometry in Therapeutic Drug Monitoring of Psychiatric Drugs. 高分辨率质谱技术在精神科药物监测中的应用。

IF 19 1区医学

Annual review of pharmacology and toxicology Pub Date : 2026-09-17 DOI: 10.1146/annurev-pharmtox-060425-092716

Espen Molden, Birgit M Wollmann, Léon Reubsaet

{"title":"Use of High-Resolution Mass Spectrometry in Therapeutic Drug Monitoring of Psychiatric Drugs.","authors":"Espen Molden, Birgit M Wollmann, Léon Reubsaet","doi":"10.1146/annurev-pharmtox-060425-092716","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060425-092716","url":null,"abstract":"Psychiatric diseases are among the most challenging health issues in terms of human suffering, complex treatments, frequent treatment failure, high degrees of disability and sick leave usage, and high social expenditure. For many patients, chronic drug treatment is often required. However, many patients experience insufficient clinical effects or side effects. Therapeutic drug monitoring (TDM) of plasma/serum concentration of psychiatric drugs aims to facilitate precision dosing and improve outcomes. High-resolution mass spectrometry (HR-MS) is a powerful technique to refine TDM with excellent specificity and sensitivity by measuring the exact mass of drugs and metabolites. The benefits of such an analytical method include that many compounds can be measured simultaneously and with short run times. Additional applications include retrospective data reprocessing to reveal interacting comedications, active/toxic metabolites, and dosing biomarkers, in which researchers reprocess exact masses of stored HR-MS TDM files. This review illustrates the benefits of HR-MS-based TDM focusing on psychiatry and innovative applications.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987791","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

Protein Synthesis Dysregulation in Neurodegeneration: Mechanisms, Consequences, and Therapeutic Modulation. 神经退行性疾病中的蛋白质合成失调：机制、后果和治疗调节。

IF 19 1区医学

Annual review of pharmacology and toxicology Pub Date : 2026-09-08 DOI: 10.1146/annurev-pharmtox-080125-105017

Karinder K Brar, Adrian J Butcher, Giovanna R Mallucci

{"title":"Protein Synthesis Dysregulation in Neurodegeneration: Mechanisms, Consequences, and Therapeutic Modulation.","authors":"Karinder K Brar, Adrian J Butcher, Giovanna R Mallucci","doi":"10.1146/annurev-pharmtox-080125-105017","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-080125-105017","url":null,"abstract":"Protein synthesis in neurons is essential for shaping and maintaining the proteome, which underpins synaptic function, learning, memory, and neuronal resilience. Dysregulated mRNA translation control, particularly at the level of initiation, results in reduced global protein synthesis and is a common pathological feature of many neurodegenerative disorders. In mouse models of these diseases, sustained global translational repression drives synaptic dysfunction and loss, ultimately leading to neurodegeneration. Crucially, interventions alleviating this repression restore the proteome, rescue synaptic dysfunction, and promote neuronal survival, leading to their therapeutic potential being assessed in clinical trials. Recently, alternative nodes of regulation have emerged, not only of global mRNA translation-including elongation control-but also of mechanisms fine-tuning subcellular translation in different cellular compartments, notably at synapses and mitochondria. These translation regulatory mechanisms bring a more nuanced understanding of the role of local protein synthesis in neuronal health and disease and the opportunity for novel therapies.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910868","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

Precision Drug Discovery in the Era of Artificial Intelligence: A Critical Review. 人工智能时代的精准药物发现：综述

IF 19 1区医学

Annual review of pharmacology and toxicology Pub Date : 2026-09-08 DOI: 10.1146/annurev-pharmtox-060325-010428

Mengya Liu, Jiacheng Xiong, Mingyue Zheng

{"title":"Precision Drug Discovery in the Era of Artificial Intelligence: A Critical Review.","authors":"Mengya Liu, Jiacheng Xiong, Mingyue Zheng","doi":"10.1146/annurev-pharmtox-060325-010428","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060325-010428","url":null,"abstract":"Traditional drug development suffers from high costs, low success rates, and patient response variability. Precision drug discovery seeks to overcome these limitations by targeting specific genetic and molecular mechanisms but faces challenges in integrating cross-scale, multimodal biomedical data. Recent advances in artificial intelligence (AI), especially deep learning, provide powerful tools to navigate these complexities. This review surveys representative AI methods across four core stages of precision drug discovery: (a) target identification and validation using omics-, drug-, and structure-based approaches; (b) structure- and sequence-guided virtual screening of active compounds; (c) individualized drug response prediction integrating cell-line, single-cell, and multimodal data; and (d) AI-enabled toxicology and safety modeling to anticipate adverse liabilities and improve translational success. We further highlight a paradigm shift toward autonomous scientific agents capable of causal reasoning and end-to-end experimental guidance. Finally, we discuss persistent challenges, including data bias, limited interpretability, and in silico-to-wet lab translation.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910894","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

New Natural Product Antibiotics: Strategies and Tools That Offer New Approaches to Overcome Traditional Roadblocks. 新的天然产物抗生素：为克服传统障碍提供新方法的策略和工具。

IF 19 1区医学

Annual review of pharmacology and toxicology Pub Date : 2026-08-27 DOI: 10.1146/annurev-pharmtox-060225-120509

Maya S B George, Marie I Balea, Gerard D Wright

{"title":"New Natural Product Antibiotics: Strategies and Tools That Offer New Approaches to Overcome Traditional Roadblocks.","authors":"Maya S B George, Marie I Balea, Gerard D Wright","doi":"10.1146/annurev-pharmtox-060225-120509","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060225-120509","url":null,"abstract":"Microbial natural products have been the cornerstone of antibiotics used in medicine since their discovery in the early twentieth century. Shaped by natural selection, natural products are privileged compounds that often target complex biological systems. Despite this success, they have increasingly been abandoned by the drug discovery industry. A principal reason for moving away from natural products is the repeated identification of common antibiotic chemical scaffolds through traditional cell-killing phenotypic assays. However, synthetic compounds have largely failed to fill the antibiotic discovery gap. Advances in genomics, bioinformatics, and analytical chemistry have, in recent years, combined to show that there is still significant chemical diversity to be explored in microbes, providing an opportunity to revisit natural products for antibiotic discovery. Sourcing compounds from rare organisms through genome mining and rapid triage using metabolomics are being used to find new compounds with novel modes of action, opening the door to a new era in antibiotic innovation.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839066","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

Making Drug Dosing Decisions Based on Therapeutic Monitoring. 基于治疗监测的给药决策。

IF 19 1区医学

Annual review of pharmacology and toxicology Pub Date : 2026-08-14 DOI: 10.1146/annurev-pharmtox-060325-032401

Leslie Z Benet, Jasleen K Sodhi

引用次数: 0

Nonaddictive Analgesia: New Approaches That Target the Hodgkin-Huxley Na_V/K_V Dyad. 非成瘾性镇痛：针对霍奇金-赫胥黎NaV/KV双偶的新方法。

IF 19 1区医学

Annual review of pharmacology and toxicology Pub Date : 2026-08-13 DOI: 10.1146/annurev-pharmtox-060325-034103

Sidharth Tyagi, Mohammad-Reza Ghovanloo, Mark Estacion, Sulayman D Dib-Hajj, Stephen G Waxman

{"title":"Nonaddictive Analgesia: New Approaches That Target the Hodgkin-Huxley NaV/KV Dyad.","authors":"Sidharth Tyagi, Mohammad-Reza Ghovanloo, Mark Estacion, Sulayman D Dib-Hajj, Stephen G Waxman","doi":"10.1146/annurev-pharmtox-060325-034103","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-060325-034103","url":null,"abstract":"Chronic pain represents a massive global health burden that is exacerbated by the limitations and liabilities of opioid therapies. This review examines the biophysical basis of nociceptor excitability, framed by the Hodgkin-Huxley dyad of opposing voltage-gated sodium (NaV) and potassium (KV) conductances. We analyze the roles of peripheral NaV isoforms (NaV1.7, NaV1.8, NaV1.9) as drivers of pathological firing and discuss the translational trajectory of NaV inhibitors, ranging from the recent clinical approval of NaV1.8-selective small molecules to the ongoing challenges facing NaV1.7-targeted programs. Beyond canonical pore blockers, we evaluate emerging modalities, including state-dependent cannabinoid modulation, targeted protein degradation, and genetic interventions. Complementing these excitatory targets, we discuss KV7 channel activators as molecular brakes capable of buffering hyperexcitability. Finally, we propose that rational comodulation of this dyad offers a mechanistically grounded pathway toward effective, nonaddictive analgesia.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757315","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

Pharmacoexposomics: The Environmental Complement to Pharmacogenomics to Advance Precision Medicine. 药物暴露组学：药物基因组学的环境补充，以推进精准医学。

IF 19 1区医学

Annual review of pharmacology and toxicology Pub Date : 2026-08-13 DOI: 10.1146/annurev-pharmtox-062624-113658

Paolo Reho, Vidhu V Thaker, Arjun P Athreya, Serge Cremers, Young-Mi Go, George Hripcsak, Xin Hu, Dean P Jones, Soon-Mi Kim, Konstantinos N Lazaridis, Shuzhao Li, Kurt D Pennell, Randolph R Singh, Douglas I Walker, Chirag J Patel, Gary W Miller, IndiPHARM Consortium

{"title":"Pharmacoexposomics: The Environmental Complement to Pharmacogenomics to Advance Precision Medicine.","authors":"Paolo Reho, Vidhu V Thaker, Arjun P Athreya, Serge Cremers, Young-Mi Go, George Hripcsak, Xin Hu, Dean P Jones, Soon-Mi Kim, Konstantinos N Lazaridis, Shuzhao Li, Kurt D Pennell, Randolph R Singh, Douglas I Walker, Chirag J Patel, Gary W Miller, IndiPHARM Consortium","doi":"10.1146/annurev-pharmtox-062624-113658","DOIUrl":"10.1146/annurev-pharmtox-062624-113658","url":null,"abstract":"Despite advances in pharmacogenomics that have led to innovative therapeutic strategies, substantial interindividual variability in drug efficacy and toxicity persists. Both endogenous and exogenous factors contribute to this unexplained variation, resulting in suboptimal treatment effectiveness, unnecessary healthcare costs, preventable mortality, and significant human suffering. The emerging field of exposomics is aimed at addressing the complex exposures that impact human health and offers an opportunity to interrogate how these exposures influence drug actions and outcomes. Here, we introduce pharmacoexposomics as a complementary framework that systematically quantifies the body's metabolic response to drug and environmental exposures using high-resolution mass spectrometry. We then present IndiPHARM (Individualized Pharmacology), a multi-institution, Advanced Research Projects Agency for Health-supported platform designed to integrate population-scale pharmacoexposomics with pharmacogenomics and clinical data to elucidate interindividual variability in drug response, identify adverse reactions, and inform tailored, effective treatment strategies that advance precision medicine.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":""},"PeriodicalIF":19.0,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148756976","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