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Advancements in the use of xenopus oocytes for modelling neurological disease for novel drug discovery. 利用爪蟾卵母细胞模拟神经疾病以发现新药的进展。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1080/17460441.2023.2270902
Eoin C O'Connor, Kumiko Kambara, Daniel Bertrand

Introduction: Introduced about 50 years ago, the model of Xenopus oocytes for the expression of recombinant proteins has gained a broad spectrum of applications. The authors herein review the benefits brought from using this model system, with a focus on modeling neurological disease mechanisms and application to drug discovery.

Areas covered: Using multiple examples spanning from ligand gated ion channels to transporters, this review presents, in the light of the latest publications, the benefits offered from using Xenopus oocytes. Studies range from the characterization of gene mutations to the discovery of novel treatments for disorders of the central nervous system (CNS).

Expert opinion: Development of new drugs targeting CNS disorders has been marked by failures in the translation from preclinical to clinical studies. As progress in genetics and molecular biology highlights large functional differences arising from a single to a few amino acid exchanges, the need for drug screening and functional testing against human proteins is increasing. The use of Xenopus oocytes to enable precise modeling and characterization of clinically relevant genetic variants constitutes a powerful model system that can be used to inform various aspects of CNS drug discovery and development.

简介:引进非洲爪蟾卵母细胞模型约50年前,用于表达重组蛋白已获得广泛的应用。本文作者综述了使用该模型系统带来的好处,重点是对神经疾病机制进行建模并应用于药物发现。涵盖的领域:本综述使用了从配体门控离子通道到转运蛋白的多个例子,根据最新的出版物,介绍了使用非洲爪蟾卵母细胞所带来的好处。研究范围从基因突变的表征到发现中枢神经系统疾病的新治疗方法。专家意见:针对中枢神经系统障碍的新药开发在从临床前研究到临床研究的转化过程中失败。随着遗传学和分子生物学的进步凸显了由单个到几个氨基酸交换引起的巨大功能差异,对针对人类蛋白质的药物筛选和功能测试的需求正在增加。利用非洲爪蟾卵母细胞对临床相关遗传变异进行精确建模和表征,构成了一个强大的模型系统,可用于为中枢神经系统药物发现和开发的各个方面提供信息。
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引用次数: 0
Current strategic trends in drug discovery: the present as prologue. 药物发现的当前战略趋势:以现在为开端。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1080/17460441.2023.2275640
David R Janero

Introduction: Escalating costs and inherent uncertainties associated with drug discovery invite initiatives to improve its efficiency and de-risk campaigns for inventing better therapeutics. One such initiative involves recognizing and exploiting current approaches in therapeutics invention with molecular mechanisms of action that hold promise for designing and targeting new chemical entities as drugs.

Areas covered: This perspective considers the current contextual framework around three drug-discovery approaches and evaluates their potential to help identify new targets/modalities in small-molecule molecular pharmacology: diversifying ligand-directed phenotypes for G protein-coupled receptor (GPCR) pharmacotherapeutic signaling; developing therapeutic-protein degraders and stabilizers for proximity-inducing pharmacology; and mining organelle biology for druggable therapeutic targets.

Expert opinion: The contemporary drug-discovery approaches examined appear generalizable and versatile to have applications in therapeutics invention beyond those case studies discussed herein. Accordingly, they may be considered strategic trends worthy of note in advancing the field toward novel ways of addressing pharmacotherapeutically unmet medical needs.

引言:与药物发现相关的成本不断上升和固有的不确定性促使人们采取行动提高其效率,并为发明更好的治疗方法开展风险降低活动。一个这样的倡议涉及认识和利用当前的治疗方法,这些方法具有分子作用机制,有望设计和靶向新的化学实体作为药物。所涵盖的领域:这一观点考虑了目前围绕三种药物发现方法的背景框架,并评估了它们帮助确定小分子分子药理学中新靶点/模式的潜力:G蛋白偶联受体(GPCR)药物治疗信号的配体导向表型多样化;开发用于邻近诱导药理学的治疗性蛋白质降解剂和稳定剂;以及为可药用治疗靶点挖掘细胞器生物学。专家意见:所研究的当代药物发现方法似乎是可推广和通用的,在本文讨论的案例研究之外,在治疗学发明中有应用。因此,它们可能被认为是值得注意的战略趋势,有助于推动该领域以新的方式解决药物治疗未满足的医疗需求。
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引用次数: 0
How can we unlock the full potential of marine biological resources for novel drug discovery in an effective and ethical way? 我们如何才能以有效和合乎道德的方式释放海洋生物资源的全部潜力,以发现新药?
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1080/17460441.2023.2285402
Hidayat Hussain
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引用次数: 0
Advances in drug structure-activity-relationships for the development of selenium-based compounds against HIV. 硒基抗HIV药物构效关系研究进展。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1080/17460441.2023.2284830
Dazhou Shi, Shujing Xu, Dang Ding, Kai Tang, Yang Zhou, Xiangyi Jiang, Shuo Wang, Xinyong Liu, Peng Zhan

Introduction: Selenium possesses numerous advantageous properties in the field of medicine, and a variety of selenium-containing compounds have been documented to exhibit anti-HIV activity. This paper aims to categorize these compounds and conduct SAR analysis to offer guidance for drug design and optimization.

Areas covered: The authors present a comprehensive review of the reported SAR analysis conducted on selenium-based compounds against HIV, accompanied by a concise discussion regarding the pivotal role of selenium in drug development.

Expert opinion: In addition to the conventional bioisosterism strategy, advanced strategies such as covalent inhibition, fragment-based growth and drug repositioning can also be incorporated into research on selenium-containing anti-HIV drugs. Ebselen, which acts as an HIV capsid inhibitor, serves as a valuable probe compound for the discovery of novel HIV integrase inhibitors. Furthermore, it is crucial not to underestimate the potential toxicity associated with organic selenium compounds despite no reported instances of severe toxicity.

硒在医学领域具有许多有利的特性,各种含硒化合物已被证明具有抗艾滋病毒的活性。本文旨在对这些化合物进行分类并进行SAR分析,为药物设计和优化提供指导。涵盖领域:作者对硒基抗HIV化合物的SAR分析报告进行了全面回顾,并简要讨论了硒在药物开发中的关键作用。专家意见:除了传统的生物等构策略外,共价抑制、基于片段的生长和药物重新定位等先进策略也可纳入含硒抗hiv药物的研究。Ebselen作为一种HIV衣壳抑制剂,为发现新的HIV整合酶抑制剂提供了一种有价值的探针化合物。此外,至关重要的是不要低估与有机硒化合物相关的潜在毒性,尽管没有报道严重毒性的实例。
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引用次数: 0
Benford's Law and distributions for better drug design. Benford定律和更好的药物设计分布。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1080/17460441.2023.2277342
Alfonso T García-Sosa

Introduction: Modern drug discovery incorporates various tools and data, heralding the beginning of the data-driven drug design (DD) era. The distributions of chemical and physical data used for Artificial Intelligence (AI)/Machine Learning (ML) and to drive DD have thus become highly important to be understood and used effectively.

Areas covered: The authors perform a comprehensive exploration of the statistical distributions driving the data-intensive era of drug discovery, including Benford's Law in AI/ML-based DD.

Expert opinion: As the relevance of data-driven discovery escalates, we anticipate meticulous scrutiny of datasets utilizing principles like Benford's Law to enhance data integrity and guide efficient resource allocation and experimental planning. In this data-driven era of the pharmaceutical and medical industries, addressing critical aspects such as bias mitigation, algorithm effectiveness, data stewardship, effects, and fraud prevention are essential. Harnessing Benford's Law and other distributions and statistical tests in DD provides a potent strategy to detect data anomalies, fill data gaps, and enhance dataset quality. Benford's Law is a fast method for data integrity and quality of datasets, the backbone of AI/ML and other modeling approaches, proving very useful in the design process.

引言:现代药物发现融合了各种工具和数据,预示着数据驱动药物设计(DD)时代的开始。因此,用于人工智能(AI)/机器学习(ML)和驱动DD的化学和物理数据的分布对于有效理解和使用变得非常重要。涵盖的领域:作者对推动药物发现数据密集型时代的统计分布进行了全面探索,包括基于AI/ML的DD中的Benford定律。专家意见:随着数据驱动发现的相关性升级,我们预计将利用Benford定律等原理对数据集进行细致的审查,以增强数据的完整性,并指导有效的资源分配和实验规划。在这个制药和医疗行业的数据驱动时代,解决偏见缓解、算法有效性、数据管理、效果和欺诈预防等关键方面至关重要。利用Benford定律和DD中的其他分布和统计测试提供了一种有效的策略来检测数据异常、填补数据空白和提高数据集质量。Benford定律是一种快速的数据完整性和数据集质量方法,是AI/ML和其他建模方法的支柱,在设计过程中非常有用。
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引用次数: 0
Evaluating physiochemical properties of FDA-approved orally administered drugs. 评估美国食品药品监督管理局批准的口服药物的理化性质。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1080/17460441.2023.2275617
Tanner C Reese, Anvita Devineni, Tristan Smith, Ismail Lalami, Jung-Mo Ahn, Ganesh V Raj

Introduction: Analyses of orally administered FDA-approved drugs from 1990 to 1993 enabled the identification of a set of physiochemical properties known as Lipinski's Rule of Five (Ro5). The original Ro5 and extended versions still remain the reference criteria for drug development programs. Since many bioactive compounds do not conform to the Ro5, we validated the relevance of and adherence to these rulesets in a contemporary cohort of FDA-approved drugs.

Areas covered: The authors noted that a significant proportion of FDA-approved orally administered parent compounds from 2011 to 2022 deviate from the original Ro5 criteria (~38%) or the Ro5 with extensions (~53%). They then evaluated if a contemporary Ro5 criteria (cRo5) could be devised to better predict oral bioavailability. Furthermore, they discuss many case studies showcasing the need for and benefit of increasing the size of certain compounds and cover several evolving strategies for improving oral bioavailability.

Expert opinion: Despite many revisions to the Ro5, the authors find that no single proposed physiochemical rule has universal concordance with absolute oral bioavailability. Innovations in drug delivery and formulation have dramatically expanded the range of physicochemical properties and the chemical diversity for oral administration.

引言:从1990年到1993年,对美国食品药品监督管理局批准的口服药物进行分析,可以确定一组被称为利平斯基五条规则(Ro5)的理化性质。原始Ro5和扩展版本仍然是药物开发计划的参考标准。由于许多生物活性化合物不符合Ro5,我们在美国食品药品监督管理局批准的当代药物队列中验证了这些规则集的相关性和遵守性。涵盖的领域:作者指出,2011年至2022年,美国食品药品监督管理局批准的口服母体化合物中有很大一部分偏离了原始Ro5标准(约38%)或Ro5扩展标准(约53%)。然后,他们评估了是否可以制定当代Ro5标准(cRo5)来更好地预测口服生物利用度。此外,他们讨论了许多案例研究,这些研究表明了增加某些化合物的大小的必要性和益处,并涵盖了提高口服生物利用度的几种不断发展的策略。专家意见:尽管对Ro5进行了多次修订,但作者发现,没有一个单一的物理化学规则与绝对口服生物利用度具有普遍一致性。药物递送和配方的创新极大地扩大了口服给药的理化性质和化学多样性范围。
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引用次数: 0
Recent applications of positron emission tomographic (PET) imaging in psychiatric drug discovery. 正电子发射断层成像(PET)在精神药物发现中的最新应用。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1080/17460441.2023.2278635
Luc Zimmer

Introduction: Psychiatry is one of the medical disciplines that suffers most from a lack of innovation in its therapeutic arsenal. Many failures in drug candidate trials can be explained by pharmacological properties that have been poorly assessed upstream, in terms of brain passage, brain target binding and clinical outcomes. Positron emission tomography can provide pharmacokinetic and pharmacodynamic data to help select candidate-molecules for further clinical trials.

Areas covered: This review aims to explain and discuss the various methods using positron-emitting radiolabeled molecules to trace the cerebral distribution of the drug-candidate or indirectly measure binding to its therapeutic target. More than an exhaustive review of PET studies in psychopharmacology, this article highlights the contributions this technology can make in drug discovery applied to psychiatry.

Expert opinion: PET neuroimaging is the only technological approach that can, in vivo in humans, measure cerebral delivery of a drug candidate, percentage and duration of target binding, and even the pharmacological effects. PET studies in a small number of subjects in the early stages of the development of a psychotropic drug can therefore provide the pharmacokinetic/pharmacodynamic data required for subsequent clinical evaluation. While PET technology is demanding in terms of radiochemical, radiopharmacological and nuclear medicine expertise, its integration into the development process of new drugs for psychiatry has great added value.

引言:精神病学是治疗手段缺乏创新的医学学科之一。候选药物试验中的许多失败可以用上游在脑通道、脑靶点结合和临床结果方面评估不佳的药理学特性来解释。正电子发射断层扫描可以提供药代动力学和药效学数据,帮助选择候选分子进行进一步的临床试验。涵盖领域:本综述旨在解释和讨论使用正电子发射放射性标记分子来追踪候选药物的大脑分布或间接测量其与治疗靶点的结合的各种方法。这篇文章不仅仅是对精神药理学PET研究的详尽综述,还强调了这项技术在应用于精神病学的药物发现方面的贡献。专家意见:PET神经成像是唯一一种可以在人体内测量候选药物的大脑输送、靶点结合的百分比和持续时间,甚至药理学效果的技术方法。因此,在精神药物开发的早期阶段对少数受试者进行的PET研究可以提供后续临床评估所需的药代动力学/药效学数据。虽然PET技术在放射化学、放射药理学和核医学专业知识方面要求很高,但它与精神病学新药开发过程的结合具有很大的附加值。
{"title":"Recent applications of positron emission tomographic (PET) imaging in psychiatric drug discovery.","authors":"Luc Zimmer","doi":"10.1080/17460441.2023.2278635","DOIUrl":"10.1080/17460441.2023.2278635","url":null,"abstract":"<p><strong>Introduction: </strong>Psychiatry is one of the medical disciplines that suffers most from a lack of innovation in its therapeutic arsenal. Many failures in drug candidate trials can be explained by pharmacological properties that have been poorly assessed upstream, in terms of brain passage, brain target binding and clinical outcomes. Positron emission tomography can provide pharmacokinetic and pharmacodynamic data to help select candidate-molecules for further clinical trials.</p><p><strong>Areas covered: </strong>This review aims to explain and discuss the various methods using positron-emitting radiolabeled molecules to trace the cerebral distribution of the drug-candidate or indirectly measure binding to its therapeutic target. More than an exhaustive review of PET studies in psychopharmacology, this article highlights the contributions this technology can make in drug discovery applied to psychiatry.</p><p><strong>Expert opinion: </strong>PET neuroimaging is the only technological approach that can, in vivo in humans, measure cerebral delivery of a drug candidate, percentage and duration of target binding, and even the pharmacological effects. PET studies in a small number of subjects in the early stages of the development of a psychotropic drug can therefore provide the pharmacokinetic/pharmacodynamic data required for subsequent clinical evaluation. While PET technology is demanding in terms of radiochemical, radiopharmacological and nuclear medicine expertise, its integration into the development process of new drugs for psychiatry has great added value.</p>","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"161-172"},"PeriodicalIF":6.3,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72014063","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
Current views on in vivo models for breast cancer research and related drug development. 关于乳腺癌研究和相关药物开发的体内模型的当前观点。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1080/17460441.2023.2293152
Tiago Ferreira, Tiago Azevedo, Jessica Silva, Ana I Faustino-Rocha, Paula A Oliveira

Introduction: Animal models play a crucial role in breast cancer research, in particular mice and rats, who develop mammary tumors that closely resemble their human counterparts. These models allow the study of mechanisms behind breast carcinogenesis, as well as the efficacy and safety of new, and potentially more effective and advantageous therapeutic approaches. Understanding the advantages and disadvantages of each model is crucial to select the most appropriate one for the research purpose.

Area covered: This review provides a concise overview of the animal models available for breast cancer research, discussing the advantages and disadvantages of each one for searching new and more effective approaches to treatments for this type of cancer.

Expert opinion: Rodent models provide valuable information on the genetic alterations of the disease, the tumor microenvironment, and allow the evaluation of the efficacy of chemotherapeutic agents. However, in vivo models have limitations, and one of them is the fact that they do not fully mimic human diseases. Choosing the most suitable model for the study purpose is crucial for the development of new therapeutic agents that provide better care for breast cancer patients.

导言:动物模型在乳腺癌研究中发挥着至关重要的作用,尤其是小鼠和大鼠,它们所患的乳腺肿瘤与人类的乳腺肿瘤非常相似。通过这些模型可以研究乳腺癌发生的机制,以及新的和可能更有效、更有利的治疗方法的有效性和安全性。了解每种模型的优缺点对于选择最适合研究目的的模型至关重要:本综述简明扼要地概述了可用于乳腺癌研究的动物模型,讨论了每种动物模型在寻找新的、更有效的乳腺癌治疗方法方面的优缺点:啮齿类动物模型提供了有关疾病遗传改变和肿瘤微环境的宝贵信息,并允许对化疗药物的疗效进行评估。然而,体内模型也有局限性,其中之一就是不能完全模拟人类疾病。选择最适合研究目的的模型对于开发新的治疗药物,为乳腺癌患者提供更好的治疗至关重要。
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引用次数: 0
Successfully navigating the valley of death: the importance of accelerators to support academic drug discovery and development. 成功地导航死亡之谷:加速器对支持学术药物发现和开发的重要性。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1080/17460441.2023.2284824
Maaike Everts, Mark Drew

Introduction: The drug discovery and development 'valley of death' remains a challenge for promising new therapies originating from academic research laboratories. Drug discovery support centers and accelerators have been established to provide monetary and scientific support, but limited available funding along with cultural and expertise gaps remain obstacles for many promising technologies.

Areas covered: In this meta-opinion article, the authors summarize the literature around obstacles that academic drug discovery projects face, along with potential solutions and best practices. Topics covered include funding challenges, regulatory education, reproducibility, along with cultural and organizational considerations. It describes one accelerator in particular-Critical Path Institute's Translational Therapeutics Accelerator (TRxA)-that aims to overcome several of the mentioned challenges.

Expert opinion: The 'valley of death' remains a stubborn but not insurmountable part of the academic drug discovery and development landscape. Purposely designed accelerators can help, complementing more traditional intra- and extramural funding support.

药物发现和开发“死亡之谷”仍然是来自学术研究实验室的有前途的新疗法的挑战。已经建立了药物发现支持中心和加速器,以提供资金和科学支持,但有限的可用资金以及文化和专业知识差距仍然是许多有前途的技术的障碍。涵盖领域:在这篇元观点文章中,作者总结了围绕学术药物发现项目面临的障碍的文献,以及潜在的解决方案和最佳实践。涵盖的主题包括资金挑战、监管教育、可重复性以及文化和组织方面的考虑。它特别描述了一个加速器-关键路径研究所的转化治疗加速器(TRxA)-旨在克服上述几个挑战。专家意见:“死亡之谷”仍然是学术药物发现和开发领域中一个顽固但并非不可逾越的部分。有意设计的加速器可以提供帮助,补充更传统的校内和校外资金支持。
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引用次数: 0
The problem of antimalarial resistance and its implications for drug discovery. 抗疟药物抗药性问题及其对药物研发的影响。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1080/17460441.2023.2284820
Thomas Martin Schäfer, Lais Pessanha de Carvalho, Juliana Inoue, Andrea Kreidenweiss, Jana Held

Introduction: Malaria remains a devastating infectious disease with hundreds of thousands of casualties each year. Antimalarial drug resistance has been a threat to malaria control and elimination for many decades and is still of concern today. Despite the continued effectiveness of current first-line treatments, namely artemisinin-based combination therapies, the emergence of drug-resistant parasites in Southeast Asia and even more alarmingly the occurrence of resistance mutations in Africa is of great concern and requires immediate attention.

Areas covered: A comprehensive overview of the mechanisms underlying the acquisition of drug resistance in Plasmodium falciparum is given. Understanding these processes provides valuable insights that can be harnessed for the development and selection of novel antimalarials with reduced resistance potential. Additionally, strategies to mitigate resistance to antimalarial compounds on the short term by using approved drugs are discussed.

Expert opinion: While employing strategies that utilize already approved drugs may offer a prompt and cost-effective approach to counter antimalarial drug resistance, it is crucial to recognize that only continuous efforts into the development of novel antimalarial drugs can ensure the successful treatment of malaria in the future. Incorporating resistance propensity assessment during this developmental process will increase the likelihood of effective and enduring malaria treatments.

导言:疟疾仍然是一种毁灭性传染病,每年造成数十万人死亡。几十年来,抗疟药物的抗药性一直威胁着疟疾的控制和消除,如今仍然令人担忧。尽管目前的一线治疗(即青蒿素类复方疗法)依然有效,但东南亚出现的抗药性寄生虫以及非洲出现的更令人震惊的抗药性突变,令人深感忧虑,需要立即引起重视:全面概述了恶性疟原虫获得抗药性的机制。对这些过程的了解提供了宝贵的见解,可用于开发和选择抗药性可能性较低的新型抗疟药物。此外,还讨论了通过使用已获批准的药物在短期内减轻抗疟药物抗药性的策略:专家观点:虽然采用使用已获批准药物的策略可以迅速、经济有效地解决抗疟药物耐药性问题,但必须认识到,只有不断努力开发新型抗疟药物,才能确保今后成功治疗疟疾。在这一研发过程中纳入抗药性倾向评估,将增加有效和持久治疗疟疾的可能性。
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引用次数: 0
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Expert Opinion on Drug Discovery
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