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Expert Opinion on Drug Discovery最新文献

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Polypharmacology prediction: the long road toward comprehensively anticipating small-molecule selectivity to de-risk drug discovery. 多药理学预测:全面预测小分子选择性以降低药物研发风险的漫长之路。
IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-01 Epub Date: 2024-07-14 DOI: 10.1080/17460441.2024.2376643
Leticia Manen-Freixa, Albert A Antolin

Introduction: Small molecules often bind to multiple targets, a behavior termed polypharmacology. Anticipating polypharmacology is essential for drug discovery since unknown off-targets can modulate safety and efficacy - profoundly affecting drug discovery success. Unfortunately, experimental methods to assess selectivity present significant limitations and drugs still fail in the clinic due to unanticipated off-targets. Computational methods are a cost-effective, complementary approach to predict polypharmacology.

Areas covered: This review aims to provide a comprehensive overview of the state of polypharmacology prediction and discuss its strengths and limitations, covering both classical cheminformatics methods and bioinformatic approaches. The authors review available data sources, paying close attention to their different coverage. The authors then discuss major algorithms grouped by the types of data that they exploit using selected examples.

Expert opinion: Polypharmacology prediction has made impressive progress over the last decades and contributed to identify many off-targets. However, data incompleteness currently limits most approaches to comprehensively predict selectivity. Moreover, our limited agreement on model assessment challenges the identification of the best algorithms - which at present show modest performance in prospective real-world applications. Despite these limitations, the exponential increase of multidisciplinary Big Data and AI hold much potential to better polypharmacology prediction and de-risk drug discovery.

简介:小分子药物通常与多个靶点结合,这种行为被称为多药理作用。预测多药理作用对药物发现至关重要,因为未知的非靶点会影响药物的安全性和有效性,从而严重影响药物发现的成功率。遗憾的是,评估选择性的实验方法存在很大的局限性,药物在临床上仍会因未预期的非靶点而失败。计算方法是预测多药理作用的一种具有成本效益的补充方法:本综述旨在全面概述多药理预测的现状,并讨论其优势和局限性,涵盖经典的化学信息学方法和生物信息学方法。作者回顾了现有的数据源,并密切关注其不同的覆盖范围。然后,作者根据所利用的数据类型,通过精选实例对主要算法进行了讨论:过去几十年来,多药理学预测取得了令人瞩目的进展,为确定许多非靶点做出了贡献。然而,数据的不完整性目前限制了大多数方法全面预测选择性。此外,我们在模型评估方面达成的一致意见有限,这对确定最佳算法提出了挑战--目前这些算法在未来的实际应用中表现一般。尽管存在这些局限性,但多学科大数据和人工智能的指数级增长为更好地进行多药理学预测和降低药物发现风险带来了巨大潜力。
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引用次数: 0
How to correctly develop q-RASAR models for predictive cheminformatics. 如何正确开发用于预测化学信息学的 q-RASAR 模型。
IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-01 Epub Date: 2024-07-05 DOI: 10.1080/17460441.2024.2376651
Arkaprava Banerjee, Kunal Roy
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引用次数: 0
Complementary strategies to be used in conjunction with animal models for multiple sclerosis drug discovery: adapting preclinical validation of drug candidates to the need of remyelinating strategies. 多发性硬化症药物研发中与动物模型结合使用的补充策略:根据再髓鞘化策略的需要对候选药物进行临床前验证。
IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-01 Epub Date: 2024-07-22 DOI: 10.1080/17460441.2024.2382180
Imane Charmarke-Askar, Caroline Spenlé, Dominique Bagnard

Introduction: The quest for novel MS therapies focuses on promoting remyelination and neuroprotection, necessitating innovative drug design paradigms and robust preclinical validation methods to ensure efficient clinical translation. The complexity of new drugs action mechanisms is strengthening the need for solid biological validation attempting to address all possible pitfalls and biases precluding access to efficient and safe drugs.

Areas covered: In this review, the authors describe the different in vitro and in vivo models that should be used to create an integrated approach for preclinical validation of novel drugs, including the evaluation of the action mechanism. This encompasses 2D, 3D in vitro models and animal models presented in such a way to define the appropriate use in a global process of drug screening and hit validation.

Expert opinion: None of the current available tests allow the concomitant evaluation of anti-inflammatory, immune regulators or remyelinating agents with sufficient reliability. Consequently, the collaborative efforts of academia, industry, and regulatory agencies are essential for establishing standardized protocols, validating novel methodologies, and translating preclinical findings into clinically meaningful outcomes.

导言:寻求新型多发性硬化症疗法的重点是促进髓鞘再形成和神经保护,这需要创新的药物设计范例和稳健的临床前验证方法,以确保高效的临床转化。新药作用机制的复杂性加强了对扎实的生物学验证的需求,试图解决所有可能的隐患和偏差,以获得高效安全的药物:在这篇综述中,作者介绍了不同的体外和体内模型,这些模型应被用于创建一种综合方法来进行新药的临床前验证,包括对作用机制的评估。其中包括二维、三维体外模型和动物模型,以确定在药物筛选和疗效验证的全过程中如何合理使用:专家意见:目前可用的检测方法中,没有一种能同时对抗炎药物、免疫调节剂或再髓鞘药物进行充分可靠的评估。因此,学术界、业界和监管机构的共同努力对于建立标准化方案、验证新方法以及将临床前研究结果转化为有临床意义的结果至关重要。
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引用次数: 0
What impact does tautomerism have on drug discovery and development? 同分异构对药物研发有何影响?
IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-01 Epub Date: 2024-07-16 DOI: 10.1080/17460441.2024.2379873
Devendra K Dhaked, Marc C Nicklaus
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引用次数: 0
An update on the novel methods for the discovery of antiseizure and antiepileptogenic medications: where are we in 2024? 发现抗癫痫和抗致痫药物新方法的最新进展:2024 年我们在哪里?
IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 Epub Date: 2024-07-04 DOI: 10.1080/17460441.2024.2373165
Alan Talevi, Carolina Bellera

Introduction: Despite the availability of around 30 antiseizure medications, 1/3 of patients with epilepsy fail to become seizure-free upon pharmacological treatment. Available medications provide adequate symptomatic control in two-thirds of patients, but disease-modifying drugs are still scarce. Recently, though, new paradigms have been explored.

Areas covered: Three areas are reviewed in which a high degree of innovation in the search for novel antiseizure and antiepileptogenic medications has been implemented: development of novel screening approaches, search for novel therapeutic targets, and adoption of new drug discovery paradigms aligned with a systems pharmacology perspective.

Expert opinion: In the past, worldwide leaders in epilepsy have reiteratively stated that the lack of progress in the field may be explained by the recurrent use of the same molecular targets and screening procedures to identify novel medications. This landscape has changed recently, as reflected by the new Epilepsy Therapy Screening Program and the introduction of many in vitro and in vivo models that could possibly improve our chances of identifying first-in-class medications that may control drug-resistant epilepsy or modify the course of disease. Other milestones include the study of new molecular targets for disease-modifying drugs and exploration of a systems pharmacology perspective to design new drugs.

简介尽管目前已有约 30 种抗癫痫药物,但仍有三分之一的癫痫患者在接受药物治疗后无法摆脱癫痫发作。现有药物可为三分之二的患者提供适当的症状控制,但改变病情的药物仍然稀缺。不过,最近人们已经开始探索新的范例:综述了在寻找新型抗癫痫和抗致痫药物方面进行了高度创新的三个领域:开发新型筛选方法、寻找新型治疗靶点以及采用与系统药理学观点相一致的新药发现范式:过去,全球癫痫领域的领军人物曾重申,该领域缺乏进展的原因可能是反复使用相同的分子靶点和筛选程序来确定新药。新的癫痫治疗筛选计划以及许多体外和体内模型的引入反映出这一情况在最近发生了变化,这些模型有可能提高我们发现一流药物的机会,从而控制耐药癫痫或改变病程。其他里程碑事件还包括研究改变病情药物的新分子靶点,以及探索从系统药理学角度设计新药物。
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引用次数: 0
An update on lipophilic efficiency as an important metric in drug design. 亲脂效率作为药物设计重要指标的最新进展。
IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 Epub Date: 2024-06-26 DOI: 10.1080/17460441.2024.2368744
Rebecca A Gallego, Martin P Edwards, T Patrick Montgomery

Introduction: Lipophilic efficiency (LipE) and lipophilic metabolic efficiency (LipMetE) are valuable tools that can be utilized as part of a multiparameter optimization process to advance a hit to a clinical quality compound.

Areas covered: This review covers recent, effective use cases of LipE and LipMetE that have been published in the literature over the past 5 years. These use cases resulted in the delivery of high-quality molecules that were brought forward to in vivo work and/or to clinical studies. The authors discuss best-practices for using LipE and LipMetE analysis, combined with lipophilicity-focused compound design strategies, to increase the speed and effectiveness of the hit to clinical quality compound optimization process.

Expert opinion: It has become well established that increasing LipE and LipMetE within a series of analogs facilitates the improvement of broad selectivity, clearance, solubility, and permeability and, through this optimization, also facilitates the achievement of desired pharmacokinetic properties, efficacy, and tolerability. Within this article, we discuss lipophilic efficiency-focused optimization as a tool to yield high-quality potential clinical candidates. It is suggested that LipE/LipMetE-focused optimization can facilitate and accelerate the drug-discovery process.

简介:亲脂效率(LipE)和亲脂代谢效率(LipMetE)是非常有价值的工具,可作为多参数优化过程的一部分,将命中化合物提升为临床优质化合物:本综述涵盖过去 5 年文献中发表的 LipE 和 LipMetE 的最新有效用例。这些使用案例产生了高质量的分子,并将其用于体内工作和/或临床研究。作者讨论了使用 LipE 和 LipMetE 分析的最佳实践,结合以亲油性为重点的化合物设计策略,以提高从命中到临床优质化合物优化过程的速度和有效性:在一系列类似物中增加 LipE 和 LipMetE 有助于提高广泛的选择性、清除率、溶解度和渗透性,而且通过这种优化,还有助于实现理想的药代动力学特性、疗效和耐受性,这一点已得到公认。在这篇文章中,我们讨论了以亲脂效率为重点的优化,将其作为一种工具来产生高质量的潜在临床候选药物。我们认为,以 LipE/LipMetE 为重点的优化可以促进和加快药物发现过程。
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引用次数: 0
The preclinical discovery and development of zolbetuximab for the treatment of gastric cancer. 用于治疗胃癌的唑贝妥昔单抗的临床前发现和开发。
IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 Epub Date: 2024-06-26 DOI: 10.1080/17460441.2024.2370332
Yongji Zeng, A Craig Lockhart, Ramon U Jin

Introduction: Gastric cancer remains a formidable challenge in oncology with high mortality rates and few advancements in treatment. Claudin-18.2 (CLDN18.2) is a tight junction protein primarily expressed in the stomach and is frequently overexpressed in certain subsets of gastric cancers. Targeting CLDN18.2 with monoclonal antibodies, such as zolbetuximab (IMAB362), has shown promising efficacy results in combination with chemotherapy.

Areas covered: The molecular cell biology of CLDN18.2 is discussed along with studies demonstrating the utility of CLDN18.2 expression as a biomarker and therapeutic target. Important clinical studies are reviewed, including Phase III trials, SPOTLIGHT and GLOW, which demonstrate the efficacy of zolbetuximab in combination with chemotherapy in patients with CLDN18.2-positive advanced gastric cancer.

Expert opinion: CLDN18.2 is involved in gastric differentiation through maintenance of epithelial barrier function and coordination of signaling pathways, and its expression in gastric cancers reflects a 'gastric differentiation' program. Targeting Claudin-18.2 represents the first gastric cancer specific 'targeted' treatment. Further studies are needed to determine its role within current gastric cancer treatment sequencing, including HER2-targeted therapies and immunotherapies. Management strategies will also be needed to better mitigate zolbetuximab-related treatment side effects, including gastrointestinal (GI) toxicities.

前言胃癌仍然是肿瘤学领域的一项艰巨挑战,死亡率高,而治疗方面却鲜有进展。Claudin-18.2(CLDN18.2)是一种主要在胃中表达的紧密连接蛋白,在某些胃癌亚型中经常过度表达。用单克隆抗体(如唑贝妥昔单抗(IMAB362))靶向 CLDN18.2,与化疗联合治疗显示出良好的疗效:讨论了 CLDN18.2 的分子细胞生物学,以及证明 CLDN18.2 表达作为生物标记物和治疗靶点的实用性的研究。回顾了重要的临床研究,包括III期试验 "SPOTLIGHT "和 "GLOW",这些试验证明了唑贝妥昔单抗联合化疗对CLDN18.2阳性晚期胃癌患者的疗效:CLDN18.2通过维持上皮屏障功能和协调信号通路参与胃分化,它在胃癌中的表达反映了 "胃分化 "程序。以Claudin-18.2为靶点是首个胃癌特异性 "靶向 "治疗方法。还需要进一步研究以确定其在当前胃癌治疗排序中的作用,包括 HER2 靶向疗法和免疫疗法。还需要制定管理策略,以更好地减轻唑贝妥昔单抗相关的治疗副作用,包括胃肠道(GI)毒性。
{"title":"The preclinical discovery and development of zolbetuximab for the treatment of gastric cancer.","authors":"Yongji Zeng, A Craig Lockhart, Ramon U Jin","doi":"10.1080/17460441.2024.2370332","DOIUrl":"10.1080/17460441.2024.2370332","url":null,"abstract":"<p><strong>Introduction: </strong>Gastric cancer remains a formidable challenge in oncology with high mortality rates and few advancements in treatment. Claudin-18.2 (CLDN18.2) is a tight junction protein primarily expressed in the stomach and is frequently overexpressed in certain subsets of gastric cancers. Targeting CLDN18.2 with monoclonal antibodies, such as zolbetuximab (IMAB362), has shown promising efficacy results in combination with chemotherapy.</p><p><strong>Areas covered: </strong>The molecular cell biology of CLDN18.2 is discussed along with studies demonstrating the utility of CLDN18.2 expression as a biomarker and therapeutic target. Important clinical studies are reviewed, including Phase III trials, SPOTLIGHT and GLOW, which demonstrate the efficacy of zolbetuximab in combination with chemotherapy in patients with CLDN18.2-positive advanced gastric cancer.</p><p><strong>Expert opinion: </strong>CLDN18.2 is involved in gastric differentiation through maintenance of epithelial barrier function and coordination of signaling pathways, and its expression in gastric cancers reflects a 'gastric differentiation' program. Targeting Claudin-18.2 represents the first gastric cancer specific 'targeted' treatment. Further studies are needed to determine its role within current gastric cancer treatment sequencing, including HER2-targeted therapies and immunotherapies. Management strategies will also be needed to better mitigate zolbetuximab-related treatment side effects, including gastrointestinal (GI) toxicities.</p>","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":"141450175","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
Targeting guanine nucleotide exchange factors for novel cancer drug discovery. 以鸟嘌呤核苷酸交换因子为靶点,发现新型抗癌药物。
IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 Epub Date: 2024-06-17 DOI: 10.1080/17460441.2024.2368242
Sahar F Bannoura, Husain Yar Khan, Md Hafiz Uddin, Ramzi M Mohammad, Boris C Pasche, Asfar S Azmi

Introduction: Guanine nucleotide exchange factors (GEFs) regulate the activation of small GTPases (G proteins) of the Ras superfamily proteins controlling cellular functions. Ras superfamily proteins act as 'molecular switches' that are turned 'ON' by guanine exchange. There are five major groups of Ras family GTPases: Ras, Ran, Rho, Rab and Arf, with a variety of different GEFs regulating their GTP loading. GEFs have been implicated in various diseases including cancer. This makes GEFs attractive targets to modulate signaling networks controlled by small GTPases.

Areas covered: In this review, the roles and mechanisms of GEFs in malignancy are outlined. The mechanism of guanine exchange activity by GEFs on a small GTPase is illustrated. Then, some examples of GEFs that are significant in cancer are presented with a discussion on recent progress in therapeutic targeting efforts using a variety of approaches.

Expert opinion: Recently, GEFs have emerged as potential therapeutic targets for novel cancer drug development. Targeting small GTPases is challenging; thus, targeting their activation by GEFs is a promising strategy. Most GEF-targeted drugs are still in preclinical development. A deeper biological understanding of the underlying mechanisms of GEF activity and utilizing advanced technology are necessary to enhance drug discovery for GEFs in cancer.

引言鸟嘌呤核苷酸交换因子(GEF)调节控制细胞功能的 Ras 超家族蛋白的小 GTP 酶(G 蛋白)的活化。Ras 超家族蛋白就像 "分子开关",通过鸟嘌呤交换打开 "开关"。Ras 家族 GTPases 有五大类:Ras、Ran、Rho、Rab 和 Arf,它们的 GTP 负载由多种不同的 GEFs 调节。GEF 与包括癌症在内的多种疾病有关。这使得 GEFs 成为调节由小 GTP 酶控制的信号网络的有吸引力的目标:本综述概述了 GEFs 在恶性肿瘤中的作用和机制。本综述概述了GEFs在恶性肿瘤中的作用和机制,并说明了GEFs对小GTP酶进行鸟嘌呤交换活动的机制。然后,举例说明了在癌症中具有重要作用的 GEFs,并讨论了利用各种方法进行靶向治疗的最新进展:最近,GEFs 已成为新型抗癌药物开发的潜在治疗靶点。以小 GTP 酶为靶点具有挑战性;因此,以 GEFs 激活小 GTP 酶为靶点是一种很有前景的策略。大多数以 GEF 为靶点的药物仍处于临床前开发阶段。有必要从生物学角度深入了解 GEF 活性的基本机制,并利用先进的技术来促进癌症 GEF 药物的开发。
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引用次数: 0
The coming of age of cyclic peptide drugs: an update on discovery technologies. 环肽药物时代的到来:发现技术的最新进展。
IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 Epub Date: 2024-06-14 DOI: 10.1080/17460441.2024.2367024
Sophia You, Glen McIntyre, Toby Passioura

Introduction: Cyclic peptides are an established class of pharmaceuticals, with the ability to bind to a broader range of protein targets than traditional small molecules while also being capable of oral availability and cell penetration. Historically, cyclic peptide drugs have been discovered almost exclusively through natural product mining approaches; however, the last two decades have seen the development of display screening approaches capable of rapidly identifying de novo (i.e. not natural product derived) cyclic peptide ligands to targets of interest.

Areas covered: In this review, the authors describe the current clinical landscape for cyclic peptide pharmaceuticals. This article focuses on the discovery approaches that have led to the development of different classes of molecules and how the development of newer technologies, particularly phage and mRNA display, has broadened the clinical applicability of such molecules.

Expert opinion: The field of de novo cyclic peptide drug discovery is reaching maturity, with the first drugs identified through display screening approaches reaching the market in recent years. Many more are in clinical trials; however, significant technical challenges remain. Technological improvements will be required over the coming years to facilitate the identification of membrane permeable cyclic peptides capable of oral availability and targeting intracellular proteins.

简介:环肽是一类成熟的药物,与传统的小分子药物相比,它能与更广泛的蛋白质靶点结合,同时还能口服和渗透细胞。从历史上看,环肽药物几乎完全是通过天然产物挖掘方法发现的;然而,在过去的二十年里,展示筛选方法得到了发展,能够快速识别与感兴趣靶点结合的全新(即非天然产物衍生)环肽配体:在这篇综述中,作者描述了当前环肽药物的临床前景。本文重点介绍了导致开发不同类别分子的发现方法,以及更新技术(尤其是噬菌体和 mRNA 展示技术)的开发如何拓宽了此类分子的临床适用性:近年来,通过展示筛选方法确定的首批药物已进入市场。还有更多的药物正在进行临床试验;然而,巨大的技术挑战依然存在。未来几年需要改进技术,以促进能够口服和靶向细胞内蛋白质的膜渗透环肽的鉴定。
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引用次数: 0
The latest trends in peptide drug discovery and future challenges. 多肽药物发现的最新趋势和未来挑战。
IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 Epub Date: 2024-06-11 DOI: 10.1080/17460441.2024.2365969
Laszlo Otvos
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引用次数: 0
期刊
Expert Opinion on Drug Discovery
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