Expert Opinion on Drug Discovery最新文献_第5页

Unveiling dynamics of nitrogen content and selected nitrogen heterocycles in thrombin inhibitors: a ceteris paribus approach. 揭示凝血酶抑制剂中氮含量和所选氮杂环的动态变化：一种 "雌雄各半 "的方法。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-08-01 Epub Date: 2024-06-19 DOI: 10.1080/17460441.2024.2368743

Vijay H Masand, Sami Al-Hussain, Abdullah Y Alzahrani, Aamal A Al-Mutairi, Arwa Sultan Alqahtani, Abdul Samad, Ahmed M Alafeefy, Rahul D Jawarkar, Magdi E A Zaki

{"title":"Unveiling dynamics of nitrogen content and selected nitrogen heterocycles in thrombin inhibitors: a ceteris paribus approach.","authors":"Vijay H Masand, Sami Al-Hussain, Abdullah Y Alzahrani, Aamal A Al-Mutairi, Arwa Sultan Alqahtani, Abdul Samad, Ahmed M Alafeefy, Rahul D Jawarkar, Magdi E A Zaki","doi":"10.1080/17460441.2024.2368743","DOIUrl":"10.1080/17460441.2024.2368743","url":null,"abstract":"Background: Despite the progress in comprehending molecular design principles and biochemical processes associated with thrombin inhibition, there is a crucial need to optimize efforts and curtail the recurrence of synthesis-testing cycles. Nitrogen and N-heterocycles are key features of many anti-thrombin drugs. Hence, a pragmatic analysis of nitrogen and N-heterocycles in thrombin inhibitors is important throughout the drug discovery pipeline. In the present work, the authors present an analysis with a specific focus on understanding the occurrence and distribution of nitrogen and selected N-heterocycles in the realm of thrombin inhibitors.Research design and methods: A dataset comprising 4359 thrombin inhibitors is used to scrutinize various categories of nitrogen atoms such as ring, non-ring, aromatic, and non-aromatic. In addition, selected aromatic and aliphatic N-heterocycles have been analyzed.Results: The analysis indicates that ~62% of thrombin inhibitors possess five or fewer nitrogen atoms. Substituted N-heterocycles have a high occurrence, like pyrrolidine (23.24%), pyridine (20.56%), piperidine (16.10%), thiazole (9.61%), imidazole (7.36%), etc. in thrombin inhibitors.Conclusions: The majority of active thrombin inhibitors contain nitrogen atoms close to 5 and a combination of N-heterocycles like pyrrolidine, pyridine, piperidine, etc. This analysis provides crucial insights to optimize the transformation of lead compounds into potential anti-thrombin inhibitors.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426625","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

Using induced pluripotent stem cells for drug discovery in arrhythmias. 利用诱导多能干细胞发现治疗心律失常的药物。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-06-02 DOI: 10.1080/17460441.2024.2360420

Diogo Teles, Barry M Fine

{"title":"Using induced pluripotent stem cells for drug discovery in arrhythmias.","authors":"Diogo Teles, Barry M Fine","doi":"10.1080/17460441.2024.2360420","DOIUrl":"10.1080/17460441.2024.2360420","url":null,"abstract":"Introduction: Arrhythmias are disturbances in the normal rhythm of the heart and account for significant cardiovascular morbidity and mortality worldwide. Historically, preclinical research has been anchored in animal models, though physiological differences between these models and humans have limited their clinical translation. The discovery of human induced pluripotent stem cells (iPSC) and subsequent differentiation into cardiomyocyte has led to the development of new in vitro models of arrhythmias with the hope of a new pathway for both exploration of pathogenic variants and novel therapeutic discovery.Areas covered: The authors describe the latest two-dimensional in vitro models of arrhythmias, several examples of the use of these models in drug development, and the role of gene editing when modeling diseases. They conclude by discussing the use of three-dimensional models in the study of arrythmias and the integration of computational technologies and machine learning with experimental technologies.Expert opinion: Human iPSC-derived cardiomyocytes models have significant potential to augment disease modeling, drug discovery, and toxicity studies in preclinical development. While there is initial success with modeling arrhythmias, the field is still in its nascency and requires advances in maturation, cellular diversity, and readouts to emulate arrhythmias more accurately.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199467","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

Strategies for the design of analogs of auranofin endowed with anticancer potential. 设计具有抗癌潜力的乌拉诺芬类似物的策略。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-05-27 DOI: 10.1080/17460441.2024.2355329

Valentina Vitali, Lara Massai, Luigi Messori

{"title":"Strategies for the design of analogs of auranofin endowed with anticancer potential.","authors":"Valentina Vitali, Lara Massai, Luigi Messori","doi":"10.1080/17460441.2024.2355329","DOIUrl":"10.1080/17460441.2024.2355329","url":null,"abstract":"Introduction: Auranofin (AF) is a well-established, FDA-approved, antiarthritic gold drug that is currently being reevaluated for a variety of therapeutic indications through drug repurposing. AF has shown great promise as a potential anticancer agent and has been approved for a few clinical trials in cancer. The renewed interest in AF has led to extensive research into the design, preparation and biological evaluation of auranofin analogs, which may have an even better pharmacological profile than the parent drug.Areas covered: This article reviews the strategies for chemical modification of the AF scaffold. Several auranofin analogs have been prepared and characterized for medical application in the field of cancer treatment over the last 20 years. Some emerging structure-function relationships are proposed and discussed.Expert opinion: The chemical modification of the AF scaffold has been the subject of intense activity in recent years and this strategy has led to the preparation and evaluation of several AF analogs. The case of iodauranofin is a particularly promising example. The availability of homogeneous biological data for a group of AF derivatives allows some initial structure-function relationships to be proposed, which may inspire the design and synthesis of new and better AF analogs for cancer treatment.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156883","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

The preclinical discovery and development of atogepant for migraine prophylaxis. 用于偏头痛预防的阿托吉潘的临床前发现和开发。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-06-10 DOI: 10.1080/17460441.2024.2365379

Carlo Baraldi, Dagmar Beier, Paolo Martelletti, Lanfranco Pellesi

{"title":"The preclinical discovery and development of atogepant for migraine prophylaxis.","authors":"Carlo Baraldi, Dagmar Beier, Paolo Martelletti, Lanfranco Pellesi","doi":"10.1080/17460441.2024.2365379","DOIUrl":"10.1080/17460441.2024.2365379","url":null,"abstract":"Introduction: Atogepant is a selective calcitonin gene-related peptide (CGRP) receptor antagonist that is utilized in adults for the prevention of episodic and chronic migraine. Cumulative findings support the involvement of CGRP in migraine pathophysiology, and atogepant functions by competitively antagonizing CGRP receptors, which results in the inhibition of trigeminovascular nociception. The mechanism of action addresses the cause of migraine pain, providing an effective preventive treatment option.Areas covered: The key milestones in its development, including preclinical achievements, phase I, II, and III clinical trials, and regulatory approvals are reviewed. Additionally, clinical efficacy, safety profile, and tolerability of atogepant are discussed. The literature review is based on a comprehensive search of English peer-reviewed articles from various electronic databases, including PubMed and ClinicalTrials.gov.Expert opinion: The development of atogepant represents a significant breakthrough in migraine prevention, particularly due to its improved safety profile that reduces the risk of liver injury, which was a major limitation of first-generation gepants. Drug-drug interaction studies with atogepant highlight the necessity for more inclusive study populations. Given that migraine disproportionately affects females, future clinical development programs should include diverse patient demographics to ensure the findings are generalizable to all individuals suffering from migraine.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295863","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 processing for high-throughput mass spectrometry in drug discovery. 药物发现中的高通量质谱数据处理。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-05-24 DOI: 10.1080/17460441.2024.2354871

Chang Liu, Hui Zhang

{"title":"Data processing for high-throughput mass spectrometry in drug discovery.","authors":"Chang Liu, Hui Zhang","doi":"10.1080/17460441.2024.2354871","DOIUrl":"10.1080/17460441.2024.2354871","url":null,"abstract":"Introduction: High-throughput mass spectrometry that could deliver > 10 times faster sample readout speed than traditional LC-based platforms has emerged as a powerful analytical technique, enabling the rapid analysis of complex biological samples. This increased speed of MS data acquisition has brought a critical demand for automatic data processing capabilities that should match or surpass the speed of data acquisition. Those data processing capabilities should serve the different requirements of drug discovery workflows.Areas covered: This paper introduced the key steps of the automatic data processing workflows for high-throughput MS technologies. Specific examples and requirements are detailed for different drug discovery applications.Expert opinion: The demand for automatic data processing in high-throughput mass spectrometry is driven by the need to keep pace with the accelerated speed of data acquisition. The seamless integration of processing capabilities with LIMS, efficient data review mechanisms, and the exploration of future features such as real-time feedback, automatic method optimization, and AI model training is crucial for advancing the drug discovery field. As technology continues to evolve, the synergy between high-throughput mass spectrometry and intelligent data processing will undoubtedly play a pivotal role in shaping the future of high-throughput drug discovery applications.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086477","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

On-demand modular assembly for expedited PROTAC development. 按需模块化组装，加快 PROTAC 开发。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-06-06 DOI: 10.1080/17460441.2024.2364637

Ayan Mukherjee, Vilas D Kadam, Qi Miao, Wanheng Zhang, Kevin R MacKenzie, Zhi Tan, Mingxing Teng

引用次数: 0

Computer-aided drug discovery strategies for novel therapeutics for prostate cancer leveraging next-generating sequencing data. 利用下一代测序数据发现前列腺癌新型疗法的计算机辅助药物发现策略。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-06-11 DOI: 10.1080/17460441.2024.2365370

Weijie Zhang, R Stephanie Huang

{"title":"Computer-aided drug discovery strategies for novel therapeutics for prostate cancer leveraging next-generating sequencing data.","authors":"Weijie Zhang, R Stephanie Huang","doi":"10.1080/17460441.2024.2365370","DOIUrl":"10.1080/17460441.2024.2365370","url":null,"abstract":"Introduction: Prostate cancer (PC) is the most common malignancy and accounts for a significant proportion of cancer deaths among men. Although initial therapy success can often be observed in patients diagnosed with localized PC, many patients eventually develop disease recurrence and metastasis. Without effective treatments, patients with aggressive PC display very poor survival. To curb the current high mortality rate, many investigations have been carried out to identify efficacious therapeutics. Compared to de novo drug designs, computational methods have been widely employed to offer actionable drug predictions in a fast and cost-efficient way. Particularly, powered by an increasing availability of next-generation sequencing molecular profiles from PC patients, computer-aided approaches can be tailored to screen for candidate drugs.Areas covered: Herein, the authors review the recent advances in computational methods for drug discovery utilizing molecular profiles from PC patients. Given the uniqueness in PC therapeutic needs, they discuss in detail the drug discovery goals of these studies, highlighting their translational values for clinically impactful drug nomination.Expert opinion: Evolving molecular profiling techniques may enable new perspectives for computer-aided approaches to offer drug candidates for different tumor microenvironments. With ongoing efforts to incorporate new compounds into large-scale high-throughput screens, the authors envision continued expansion of drug candidate pools.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300483","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

Bridging the gap between target-based and phenotypic-based drug discovery. 缩小基于靶标和基于表型的药物发现之间的差距。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-05-15 DOI: 10.1080/17460441.2024.2355330

Cecília R C Calado

{"title":"Bridging the gap between target-based and phenotypic-based drug discovery.","authors":"Cecília R C Calado","doi":"10.1080/17460441.2024.2355330","DOIUrl":"10.1080/17460441.2024.2355330","url":null,"abstract":"Introduction: The unparalleled progress in science of the last decades has brought a better understanding of the molecular mechanisms of diseases. This promoted drug discovery processes based on a target approach. However, despite the high promises associated, a critical decrease in the number of first-in-class drugs has been observed.Areas covered: This review analyses the challenges, advances, and opportunities associated with the main strategies of the drug discovery process, i.e. based on a rational target approach and on an empirical phenotypic approach. This review also evaluates how the gap between these two crossroads can be bridged toward a more efficient drug discovery process.Expert opinion: The critical lack of knowledge of the complex biological networks is leading to targets not relevant for the clinical context or to drugs that present undesired adverse effects. The phenotypic systems designed by considering available molecular mechanisms can mitigate these knowledge gaps. Associated with the expansion of the chemical space and other technologies, these designs can lead to more efficient drug discoveries. Technological and scientific knowledge should also be applied to identify, as early as possible, both drug targets and mechanisms of action, leading to a more efficient drug discovery pipeline.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920709","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

Inclisiran: the preclinical discovery and development of a novel therapy for the treatment of atherosclerosis. Inclisiran：治疗动脉粥样硬化的新型疗法的临床前发现和开发。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-05-28 DOI: 10.1080/17460441.2024.2360415

Donatos Tsamoulis, Loukianos S Rallidis, Constantine E Kosmas

{"title":"Inclisiran: the preclinical discovery and development of a novel therapy for the treatment of atherosclerosis.","authors":"Donatos Tsamoulis, Loukianos S Rallidis, Constantine E Kosmas","doi":"10.1080/17460441.2024.2360415","DOIUrl":"10.1080/17460441.2024.2360415","url":null,"abstract":"Introduction: Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of global morbidity and mortality. Lipid lowering therapy (LLT) constitutes the cornerstone of ASCVD prevention and treatment. However, several patients fail to achieve therapeutic goals due to low treatment adherence or limitations of standard-of-care (SoC) LLTs. Inclisiran represents a pivotal low-density lipoprotein cholesterol (LDL-C) lowering agent aiming to address current unmet needs in LLT. It is the first available small interfering RNA (siRNA) LLT, specifically targeting PCSK9 mRNA and leading to post-transcriptional gene silencing (PTGS) of the PCSK9 gene.Areas covered: Promising phase III trials revealed an ~ 50% reduction in LDL-C levels with subcutaneous inclisiran administration on days 1 and 90, followed by semiannual booster shots. Coupled with inclisiran's favorable safety profile, these findings led to its approval by both the EMA and FDA. Herein, the authors highlight the preclinical discovery and development of this agent and provide the reader with their expert perspectives.Expert opinion: The evolution of gene-silencing treatments offers new perspectives in therapeutics. Inclisiran appears to have the potential to revolutionize ASCVD prevention and treatment, benefiting millions of patients. Ensuring widespread availability of Inclisiran, as well as managing additional healthcare costs that may arise, should be of paramount importance.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156812","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

Hydrophobic tagging of small molecules: an overview of the literature and future outlook. 小分子的疏水标记：文献综述与未来展望。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-06-02 DOI: 10.1080/17460441.2024.2360416

Yang Zhou, Fan Zhou, Shujing Xu, Dazhou Shi, Dang Ding, Shuo Wang, Vasanthanathan Poongavanam, Kai Tang, Xinyong Liu, Peng Zhan

{"title":"Hydrophobic tagging of small molecules: an overview of the literature and future outlook.","authors":"Yang Zhou, Fan Zhou, Shujing Xu, Dazhou Shi, Dang Ding, Shuo Wang, Vasanthanathan Poongavanam, Kai Tang, Xinyong Liu, Peng Zhan","doi":"10.1080/17460441.2024.2360416","DOIUrl":"10.1080/17460441.2024.2360416","url":null,"abstract":"Introduction: Hydrophobic tagging (HyT) technology presents a distinct therapeutic strategy diverging from conventional small molecule drugs, providing an innovative approach to drug design. This review aims to provide an overview of the HyT literature and future outlook to offer guidance for drug design.Areas covered: In this review, the authors introduce the composition, mechanisms and advantages of HyT technology, as well as summarize the detailed applications of HyT technology in anti-cancer, neurodegenerative diseases (NDs), autoimmune disorders, cardiovascular diseases (CVDs), and other fields. Furthermore, this review discusses key aspects of the future development of HyT molecules.Expert opinion: HyT emerges as a highly promising targeted protein degradation (TPD) strategy, following the successful development of proteolysis targeting chimeras (PROTAC) and molecular glue. Based on exploring new avenues, modification of the HyT molecule itself potentially enhances the technology. Improved synthetic pathways and emphasis on pharmacokinetic (PK) properties will facilitate the development of HyT. Furthermore, elucidating the biochemical basis by which the compound's hydrophobic moiety recruits the protein homeostasis network will enable the development of more precise assays that can guide the optimization of the linker and hydrophobic moiety.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199460","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