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Which cryptic sites are feasible drug targets? 哪些隐匿位点是可行的药物靶点？
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-10-04 DOI: 10.1016/j.drudis.2024.104197
Maria Lazou , Dima Kozakov , Diane Joseph-McCarthy , Sandor Vajda
{"title":"Which cryptic sites are feasible drug targets?","authors":"Maria Lazou ,&nbsp;Dima Kozakov ,&nbsp;Diane Joseph-McCarthy ,&nbsp;Sandor Vajda","doi":"10.1016/j.drudis.2024.104197","DOIUrl":"10.1016/j.drudis.2024.104197","url":null,"abstract":"<div><div>Cryptic sites can expand the space of druggable proteins, but the potential usefulness of such sites needs to be investigated before any major effort. Given that the binding pockets are not formed, the druggability of such sites is not well understood. The analysis of proteins and their ligands shows that cryptic sites that are formed primarily by the motion of side chains moving out of the pocket to enable ligand binding generally do not bind drug-sized molecules with sufficient potency. By contrast, sites that are formed by loop or hinge motion are potentially valuable drug targets. Arguments are provided to explain the underlying causes in terms of classical enzyme inhibition theory and the kinetics of side chain motion and ligand binding.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104197"},"PeriodicalIF":6.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378854","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
3D light-sheet fluorescence microscopy in preclinical and clinical drug discovery 三维光片荧光显微镜在临床前和临床药物发现中的应用。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-10-04 DOI: 10.1016/j.drudis.2024.104196
Urmas Roostalu, Henrik H. Hansen, Jacob Hecksher-Sørensen
{"title":"3D light-sheet fluorescence microscopy in preclinical and clinical drug discovery","authors":"Urmas Roostalu,&nbsp;Henrik H. Hansen,&nbsp;Jacob Hecksher-Sørensen","doi":"10.1016/j.drudis.2024.104196","DOIUrl":"10.1016/j.drudis.2024.104196","url":null,"abstract":"<div><div>Light-sheet fluorescence microscopy (LSFM) combined with tissue clearing has emerged as a powerful technology in drug discovery. LSFM is applicable to a variety of samples, from rodent organs to clinical tissue biopsies, and has been used for characterizing drug targets in tissues, demonstrating the biodistribution of pharmaceuticals and determining their efficacy and mode of action. LSFM is scalable to high-throughput analysis and provides resolution down to the single cell level. In this review, we describe the advantages of implementing LSFM into the drug discovery pipeline and highlight recent advances in this field.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104196"},"PeriodicalIF":6.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378852","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
Heat shock protein 110: A novel candidate for disease diagnosis and targeted therapy 热休克蛋白 110：疾病诊断和靶向治疗的新候选者。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-10-04 DOI: 10.1016/j.drudis.2024.104199
Congke Zhao , Honglin Xiang , Mengqi Li , Ruizhe Gao , Yifan Zhang , Qianbin Li , Liqing Hu
{"title":"Heat shock protein 110: A novel candidate for disease diagnosis and targeted therapy","authors":"Congke Zhao ,&nbsp;Honglin Xiang ,&nbsp;Mengqi Li ,&nbsp;Ruizhe Gao ,&nbsp;Yifan Zhang ,&nbsp;Qianbin Li ,&nbsp;Liqing Hu","doi":"10.1016/j.drudis.2024.104199","DOIUrl":"10.1016/j.drudis.2024.104199","url":null,"abstract":"<div><div>The heat shock protein 110 (Hsp110) family in eukaryotes plays a pivotal role in maintaining cellular proteostasis. As a unique class of molecular chaperones, Hsp110s act as both independent chaperones and cochaperones for other essential molecular chaperones. Malfunction of Hsp110s is involved in many diseases. Thus targeting Hsp110s or its interactions with client proteins may provide new approaches for developing therapeutics. In this review, we describe the current understanding of the role and molecular mechanism of Hsp110s in disease development, and discuss the recent exploration of Hsp110s as potential targets to provide a novel direction for disease diagnosis and targeted therapy.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 12","pages":"Article 104199"},"PeriodicalIF":6.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378853","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
Data-driven toxicity prediction in drug discovery: Current status and future directions 药物发现中数据驱动的毒性预测：现状与未来方向。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-30 DOI: 10.1016/j.drudis.2024.104195
Ningning Wang , Xinliang Li , Jing Xiao , Shao Liu , Dongsheng Cao
{"title":"Data-driven toxicity prediction in drug discovery: Current status and future directions","authors":"Ningning Wang ,&nbsp;Xinliang Li ,&nbsp;Jing Xiao ,&nbsp;Shao Liu ,&nbsp;Dongsheng Cao","doi":"10.1016/j.drudis.2024.104195","DOIUrl":"10.1016/j.drudis.2024.104195","url":null,"abstract":"<div><div>Early toxicity assessment plays a vital role in the drug discovery process on account of its significant influence on the attrition rate of candidates. Recently, constant upgrading of information technology has greatly promoted the continuous development of toxicity prediction. To give an overview of the current state of data-driven toxicity prediction, we reviewed relevant studies and summarized them in three main respects: the features and difficulties of toxicity prediction, the evolution of modeling approaches, and the available tools for toxicity prediction. For each part, we expound the research status, existing challenges, and feasible solutions. Finally, several new directions and suggestions for toxicity prediction are also put forward.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104195"},"PeriodicalIF":6.5,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363693","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
Design of bifunctional molecules to accelerate post-translational modifications: achievements and challenges 设计双功能分子以加速翻译后修饰：成就与挑战。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-28 DOI: 10.1016/j.drudis.2024.104194
Yuxuan Wang , Yanyi He , Qidong You, Lei Wang
{"title":"Design of bifunctional molecules to accelerate post-translational modifications: achievements and challenges","authors":"Yuxuan Wang ,&nbsp;Yanyi He ,&nbsp;Qidong You,&nbsp;Lei Wang","doi":"10.1016/j.drudis.2024.104194","DOIUrl":"10.1016/j.drudis.2024.104194","url":null,"abstract":"<div><div>Post-translational modifications (PTMs) of proteins are crucial for regulating biological processes and their dysregulation is linked to various diseases, highlighting PTM regulation as a significant target for drug development. Traditional drug targets often interact with multiple proteins, resulting in lower selectivity and inevitable adverse effects, which limits their clinical applicability. Recent advancements in bifunctional molecules, such as proteolysis-targeting chimeras (PROTACs), have shown promise in targeting PTMs precisely. However, regulatory mechanisms for many of the &gt;600 known PTMs remain underexplored. This review examines current progress and challenges in designing bifunctional molecules for PTM regulation, focusing on effector selection and ligand design strategies, aiming to propel the utilization and advancement of bifunctional molecules to the forefront of PTM research.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104194"},"PeriodicalIF":6.5,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338155","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
Impact of HDAC inhibitors on macrophage polarization to enhance innate immunity against infections HDAC 抑制剂对巨噬细胞极化的影响，以增强抗感染的先天免疫力。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-26 DOI: 10.1016/j.drudis.2024.104193
Mohammad Faizan Bhat , Sonja Srdanović , Lotta-Riina Sundberg , Helga Kristín Einarsdóttir , Varpu Marjomäki , Frank J. Dekker
{"title":"Impact of HDAC inhibitors on macrophage polarization to enhance innate immunity against infections","authors":"Mohammad Faizan Bhat ,&nbsp;Sonja Srdanović ,&nbsp;Lotta-Riina Sundberg ,&nbsp;Helga Kristín Einarsdóttir ,&nbsp;Varpu Marjomäki ,&nbsp;Frank J. Dekker","doi":"10.1016/j.drudis.2024.104193","DOIUrl":"10.1016/j.drudis.2024.104193","url":null,"abstract":"<div><div>Innate immunity plays an important role in host defense against pathogenic infections. It involves macrophage polarization into either the pro-inflammatory M1 or the anti-inflammatory M2 phenotype, influencing immune stimulation or suppression, respectively. Epigenetic changes during immune reactions contribute to long-term innate immunity imprinting on macrophage polarization. It is becoming increasingly evident that epigenetic modulators, such as histone deacetylase (HDAC) inhibitors (HDACi), enable the enhancement of innate immunity by tailoring macrophage polarization in response to immune stressors. In this review, we summarize current literature on the impact of HDACi and other epigenetic modulators on the functioning of macrophages during diseases that have a strong immune component, such as infections. Depending on the disease context and the chosen therapeutic intervention, HDAC1, HDAC2, HDAC3, HDAC6, or HDAC8 are particularly important in influencing macrophage polarization towards either M1 or M2 phenotypes. We anticipate that therapeutic strategies based on HDAC epigenetic mechanisms will provide a unique approach to boost immunity against disease challenges, including resistant infections.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104193"},"PeriodicalIF":6.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Promising therapeutic targets for tumor treatment: Cleaved activation of receptors in the nucleus 有希望成为肿瘤治疗靶点：细胞核中受体的裂解激活。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-25 DOI: 10.1016/j.drudis.2024.104192
Mengdie Fu, Jin He, Danji Zhu, Qinmeng Zhang, Zhiwei Jiang, Guoli Yang
{"title":"Promising therapeutic targets for tumor treatment: Cleaved activation of receptors in the nucleus","authors":"Mengdie Fu,&nbsp;Jin He,&nbsp;Danji Zhu,&nbsp;Qinmeng Zhang,&nbsp;Zhiwei Jiang,&nbsp;Guoli Yang","doi":"10.1016/j.drudis.2024.104192","DOIUrl":"10.1016/j.drudis.2024.104192","url":null,"abstract":"<div><div>A new fate of cell surface receptors, cleaved activation in the nucleus, is summarized. The intracellular domain (ICD) of cell surface receptors, cleaved by enzymes like γ-secretase, translocates to the nucleus to form transcriptional complexes participating in the onset and development of tumors. The fate is clinically significant, as inhibitors of cleavage enzymes have shown effectiveness in treating advanced tumors by reducing tumorigenic ICDs. Additionally, the construction of synthetic receptors also conforms with the fate mechanism. This review details each step of cleaved activation in the nucleus, elucidates tumorigenic mechanisms, explores application in antitumor therapy, and scrutinizes possible limitations.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104192"},"PeriodicalIF":6.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338158","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
Spotlight on HIV-derived TAT peptide as a molecular shuttle in drug delivery 聚焦作为药物输送分子穿梭器的艾滋病毒衍生 TAT 肽。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-24 DOI: 10.1016/j.drudis.2024.104191
Zahra Maani , Leila Rahbarnia , Ali Bahadori , Khalil Maleki Chollou , Safar Farajnia
{"title":"Spotlight on HIV-derived TAT peptide as a molecular shuttle in drug delivery","authors":"Zahra Maani ,&nbsp;Leila Rahbarnia ,&nbsp;Ali Bahadori ,&nbsp;Khalil Maleki Chollou ,&nbsp;Safar Farajnia","doi":"10.1016/j.drudis.2024.104191","DOIUrl":"10.1016/j.drudis.2024.104191","url":null,"abstract":"<div><div>HIV-derived TAT peptide, with a high penetration rate into cells and its nonimmunogenic and minimally toxic nature, is an attractive tool for enhancing the biodistribution of drugs and their systemic administration. Despite the presence of numerous promising preclinical investigations illustrating its capability to specifically target distinct tissues and deliver a diverse range of pharmacological agents, the efficacy of various clinical trials incorporating TAT has been impeded by several considerable obstacles. Hence, there is much need for an in-depth investigation concerning the application of TAT in drug delivery mechanisms. In this review, we have elucidated the structure of TAT and its utility in the proficient delivery of various types of bioactive molecules.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104191"},"PeriodicalIF":6.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338159","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
Downregulation of microRNA-29b in cancer and fibrosis: molecular insights and clinical implications 癌症和纤维化中 microRNA-29b 的下调：分子见解和临床意义。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-24 DOI: 10.1016/j.drudis.2024.104190
Pratik Pramod Shinde, Deepak Chitkara, Anupama Mittal
{"title":"Downregulation of microRNA-29b in cancer and fibrosis: molecular insights and clinical implications","authors":"Pratik Pramod Shinde,&nbsp;Deepak Chitkara,&nbsp;Anupama Mittal","doi":"10.1016/j.drudis.2024.104190","DOIUrl":"10.1016/j.drudis.2024.104190","url":null,"abstract":"<div><div>MicroRNA-29b (miR-29b) is known for its therapeutic potential as an antifibrotic and anticancer agent. In fibrotic conditions, miR-29b inhibits fibrogenesis by downregulating crucial regulators such as collagens, extracellular matrix proteins and the transforming growth factor-β pathway. Similarly, in cancer, it acts as a tumor suppressor by downregulating various oncogenes and signaling pathways involved in cancer progression, such as Wnt–β-catenin, p38–mitogen-activated protein kinase and nuclear factor-κB. However, the upregulation of these pathways suppresses miR-29b, contributing to fibrosis and cancer development. Preclinical research and clinical trials have shown that delivering exogenous miR-29b mimics can restore its expression, attenuating tumorigenesis and fibrogenesis. This review discusses miR-29b’s potential and its possible therapeutic development for cancer and fibrotic disorders.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104190"},"PeriodicalIF":6.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338156","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
From promise to progress: the dynamic landscape of glioblastoma immunotherapy 从希望到进步：胶质母细胞瘤免疫疗法的动态发展。
IF 6.5 2区 医学
Drug Discovery Today Pub Date : 2024-09-20 DOI: 10.1016/j.drudis.2024.104188
Muhammad Ijaz , Zia Ullah , Bilal Aslam , Mohsin Khurshid , Pengfei Chen , Bing Guo
{"title":"From promise to progress: the dynamic landscape of glioblastoma immunotherapy","authors":"Muhammad Ijaz ,&nbsp;Zia Ullah ,&nbsp;Bilal Aslam ,&nbsp;Mohsin Khurshid ,&nbsp;Pengfei Chen ,&nbsp;Bing Guo","doi":"10.1016/j.drudis.2024.104188","DOIUrl":"10.1016/j.drudis.2024.104188","url":null,"abstract":"<div><div>Glioblastoma multiforme (GBM) is the most common CNS cancer, it has dismal survival rates despite several effective mediators: intensified cytotoxic therapy, chimeric antigen receptor (CAR)-T cell therapy, viral therapy, adoptive cell therapy, immune checkpoint blockade therapy, radiation therapy and vaccine therapy. This review examines the basic concepts underlying immune targeting and examines products such as checkpoint blockade drugs, CAR-T cells, oncolytic viruses, combinatory multimodal immunotherapy and cancer vaccines. New approaches to overcoming current constraints and challenges in GBM therapy are discussed, based on recent studies into these tactics, findings from ongoing clinical trials, as well as previous trial results.</div></div>","PeriodicalId":301,"journal":{"name":"Drug Discovery Today","volume":"29 11","pages":"Article 104188"},"PeriodicalIF":6.5,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277767","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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