Expert Opinion on Drug Discovery最新文献_第2页

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

Expert Opinion on Drug Discovery Pub Date : 2024-08-01 Epub Date: 2024-07-04 DOI: 10.1080/17460441.2024.2373165

Alan Talevi, Carolina Bellera

{"title":"An update on the novel methods for the discovery of antiseizure and antiepileptogenic medications: where are we in 2024?","authors":"Alan Talevi, Carolina Bellera","doi":"10.1080/17460441.2024.2373165","DOIUrl":"10.1080/17460441.2024.2373165","url":null,"abstract":"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.","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":"141497585","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

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

Expert Opinion on Drug Discovery 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

{"title":"An update on lipophilic efficiency as an important metric in drug design.","authors":"Rebecca A Gallego, Martin P Edwards, T Patrick Montgomery","doi":"10.1080/17460441.2024.2368744","DOIUrl":"10.1080/17460441.2024.2368744","url":null,"abstract":"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.","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":"141450174","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 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

Expert Opinion on Drug Discovery Pub Date : 2024-08-01 Epub Date: 2024-06-26 DOI: 10.1080/17460441.2024.2370332

Yongji Zeng, A Craig Lockhart, Ramon U Jin

{"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":"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.","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

Expert Opinion on Drug Discovery 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

{"title":"Targeting guanine nucleotide exchange factors for novel cancer drug discovery.","authors":"Sahar F Bannoura, Husain Yar Khan, Md Hafiz Uddin, Ramzi M Mohammad, Boris C Pasche, Asfar S Azmi","doi":"10.1080/17460441.2024.2368242","DOIUrl":"10.1080/17460441.2024.2368242","url":null,"abstract":"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.","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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330729","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

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

Expert Opinion on Drug Discovery Pub Date : 2024-08-01 Epub Date: 2024-06-14 DOI: 10.1080/17460441.2024.2367024

Sophia You, Glen McIntyre, Toby Passioura

{"title":"The coming of age of cyclic peptide drugs: an update on discovery technologies.","authors":"Sophia You, Glen McIntyre, Toby Passioura","doi":"10.1080/17460441.2024.2367024","DOIUrl":"10.1080/17460441.2024.2367024","url":null,"abstract":"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.","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":"141316957","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 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

Expert Opinion on Drug Discovery Pub Date : 2024-08-01 Epub Date: 2024-06-11 DOI: 10.1080/17460441.2024.2365969

Laszlo Otvos

引用次数: 0

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

Lessons learnt from broad-spectrum coronavirus antiviral drug discovery. 广谱冠状病毒抗病毒药物研发的经验教训。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-30 DOI: 10.1080/17460441.2024.2385598

Andrew A Bolinger, Jun Li, Xuping Xie, Hongmin Li, Jia Zhou

{"title":"Lessons learnt from broad-spectrum coronavirus antiviral drug discovery.","authors":"Andrew A Bolinger, Jun Li, Xuping Xie, Hongmin Li, Jia Zhou","doi":"10.1080/17460441.2024.2385598","DOIUrl":"https://doi.org/10.1080/17460441.2024.2385598","url":null,"abstract":"Introduction: Highly pathogenic coronaviruses (CoVs), such as severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and the most recent SARS-CoV-2 responsible for the COVID-19 pandemic, pose significant threats to human populations over the past two decades. These CoVs have caused a broad spectrum of clinical manifestations ranging from asymptomatic to severe distress syndromes (ARDS), resulting in high morbidity and mortality.Areas covered: The accelerated advancements in antiviral drug discovery, spurred by the COVID-19 pandemic, have shed new light on the imperative to develop treatments effective against a broad spectrum of CoVs. This perspective discusses strategies and lessons learnt in targeting viral non-structural proteins, structural proteins, drug repurposing, and combinational approaches for the development of antivirals against CoVs.Expert opinion: Drawing lessons from the pandemic, it becomes evident that the absence of efficient broad-spectrum antiviral drugs increases the vulnerability of public health systems to the potential onslaught by highly pathogenic CoVs. The rapid and sustained spread of novel CoVs can have devastating consequences without effective and specifically targeted treatments. Prioritizing the effective development of broad-spectrum antivirals is imperative for bolstering the resilience of public health systems and mitigating the potential impact of future highly pathogenic CoVs.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792329","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

Innovative drug discovery strategies in epilepsy: integrating next-generation syndrome-specific mouse models to address pharmacoresistance and epileptogenesis. 癫痫的创新药物发现策略：整合下一代综合征特异性小鼠模型，解决抗药性和癫痫发生问题。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-29 DOI: 10.1080/17460441.2024.2384455

Melissa Barker-Haliski, Nicole A Hawkins

{"title":"Innovative drug discovery strategies in epilepsy: integrating next-generation syndrome-specific mouse models to address pharmacoresistance and epileptogenesis.","authors":"Melissa Barker-Haliski, Nicole A Hawkins","doi":"10.1080/17460441.2024.2384455","DOIUrl":"10.1080/17460441.2024.2384455","url":null,"abstract":"Introduction: Although there are numerous treatment options already available for epilepsy, over 30% of patients remain resistant to these antiseizure medications (ASMs). Historically, ASM discovery has relied on the demonstration of efficacy through the use of 'traditional' acute in vivo seizure models (e.g. maximal electroshock, subcutaneous pentylenetetrazol, and kindling). However, advances in genetic sequencing technologies and remaining medical needs for people with treatment-resistant epilepsy or special patient populations have encouraged recent efforts to identify novel compounds in syndrome-specific models of epilepsy. Syndrome-specific models, including Scn1a variant models of Dravet syndrome and APP/PS1 mice associated with familial early-onset Alzheimer's disease, have already led to the discovery of two mechanistically novel treatments for developmental and epileptic encephalopathies (DEEs), namely cannabidiol and soticlestat, respectively.Areas covered: In this review, the authors discuss how it is likely that next-generation drug discovery efforts for epilepsy will more comprehensively integrate syndrome-specific epilepsy models into early drug discovery providing the reader with their expert perspectives.Expert opinion: The percentage of patients with pharmacoresistant epilepsy has remained unchanged despite over 30 marketed ASMs. Consequently, there is a high unmet need to reinvent and revise discovery strategies to more effectively address the remaining needs of patients with specific epilepsy syndromes, including drug-resistant epilepsy and DEEs.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792328","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

How to address the complexity of multi-targeted drug discovery for Alzheimer's disease? 如何应对阿尔茨海默病多靶点药物研发的复杂性？

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-29 DOI: 10.1080/17460441.2024.2385576

Juan F González, José M Sánchez-Montero

引用次数: 0