Expert Opinion on Drug Discovery最新文献_第6页

Scaffold hopping approaches for dual-target antitumor drug discovery: opportunities and challenges. 双靶点抗肿瘤药物发现的支架跳跃方法：机遇与挑战。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-11-01 Epub Date: 2024-10-17 DOI: 10.1080/17460441.2024.2409674

Anshul Mishra, Amandeep Thakur, Ram Sharma, Raphael Onuku, Charanjit Kaur, Jing Ping Liou, Sung-Po Hsu, Kunal Nepali

{"title":"Scaffold hopping approaches for dual-target antitumor drug discovery: opportunities and challenges.","authors":"Anshul Mishra, Amandeep Thakur, Ram Sharma, Raphael Onuku, Charanjit Kaur, Jing Ping Liou, Sung-Po Hsu, Kunal Nepali","doi":"10.1080/17460441.2024.2409674","DOIUrl":"10.1080/17460441.2024.2409674","url":null,"abstract":"Introduction: Scaffold hopping has emerged as a practical tactic to enrich the synthetic bank of small molecule antitumor agents. Specifically, it enables the chemist to refine the lead compound's pharmacodynamic, pharmacokinetic, and physiochemical properties. Scaffold hopping opens up fresh molecular territory beyond established patented chemical domains.Area covered: The authors present the scaffold hopping-based drug design strategies for dual inhibitory antitumor structural templates in this review. Minor modifications, structure rigidification and simplification (ring-closing and opening), and complete structural overhauls were the strategies employed by the medicinal chemist to generate a library of bifunctional inhibitors. In addition, the review presents an overview of the computational methods of scaffold hopping (software and programs) and organopalladium catalysis leveraged for the synthesis of templates designed via scaffold hopping.Expert opinion: The medicinal chemist has demonstrated remarkable prowess in furnishing dual inhibitory antitumor chemical architectures. Scaffold hopping-based drug design strategies have yielded a plethora of pharmacodynamically superior dual modulatory antitumor agents. An integrated approach involving computational advancements, synthetic methodology advancements, and conventional drug design strategies is required to increase the number of scaffold-hopping-assisted drug discovery campaigns.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1355-1381"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461546","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 AGAT gene expression - a drug screening approach for the treatment of GAMT deficiency. 靶向 AGAT 基因表达--治疗 GAMT 缺乏症的药物筛选方法。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-11-01 Epub Date: 2024-10-15 DOI: 10.1080/17460441.2024.2412994

Ilona Tkachyova, Michael B Tropak, Alex Lee, Alessandro Datti, Shinya Ito, Andreas Schulze

{"title":"Targeting AGAT gene expression - a drug screening approach for the treatment of GAMT deficiency.","authors":"Ilona Tkachyova, Michael B Tropak, Alex Lee, Alessandro Datti, Shinya Ito, Andreas Schulze","doi":"10.1080/17460441.2024.2412994","DOIUrl":"10.1080/17460441.2024.2412994","url":null,"abstract":"Background: Targeting the enzyme L-Arginine:glycine amidinotransferase (AGAT) to reduce the formation of guanidinoacetate (GAA) in patients with guanidinoacetate methyltransferase (GAMT) deficiency, we attempted to identify drugs for repurposing that reduce the expression of AGAT via transcriptional inhibition.Research design and methods: The authors applied a HeLa cell line stably expressing AGAT promoter and firefly luciferase reporter for high-content screening and secondary screening. For further assessment, the authors integrated Nanoluc luciferase as a reporter into the endogenous AGAT gene in HAP1 cell lines and used the human immortalized cell line RH30 as model of GAMT deficiency.Results: Screening 6,000 drugs and drug-like compounds, the authors identified 43 and 34 high-score candidates as inhibitors and inducers of AGAT promoter-reporter expression, respectively. After further deselection considering dose response, drug toxicity, topical formulations, price, and accessibility, the authors assessed seven candidates and found none of them demonstrating efficacy in HAP1 and RH30 cells and warranting further assessment.Conclusion: The selection of the test models is crucial for screening of gene repressor drugs. Almost all drugs with an impact on gene expression had off-target effects. It is unlikely to find drugs that are selective inhibitors of AGAT expression, rendering pharmacological AGAT gene repression a risky approach for the treatment of GAMT deficiency.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1383-1397"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461547","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

Correction. 更正。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-11-01 Epub Date: 2024-09-17 DOI: 10.1080/17460441.2024.2406102

引用次数: 0

Application of transporter assays for drug discovery and development: an update of the literature. 转运体检测在药物发现和开发中的应用：文献更新。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-10-01 Epub Date: 2024-08-06 DOI: 10.1080/17460441.2024.2387790

Donna A Volpe

{"title":"Application of transporter assays for drug discovery and development: an update of the literature.","authors":"Donna A Volpe","doi":"10.1080/17460441.2024.2387790","DOIUrl":"10.1080/17460441.2024.2387790","url":null,"abstract":"Introduction: Determining whether a new drug is a substrate, inhibitor or inducer of efflux or uptake membrane transporters has become a routine process during drug discovery and development. In vitro assays are utilized to establish whether a new drug has the potential to be an object (substrate) or precipitant (inhibitor, inducer) in transporter-mediated clinical drug-drug interactions. The findings from these in vitro experiments are then used to determine whether further in vivo drug interaction studies are necessary for a new drug.Areas covered: This article provides an update on in vitro transporter assays, focusing on new uses of transfected cells, time-dependent inhibition, transporter induction, and complex model systems.Expert opinion: The newer in vitro assays add to the toolbox in defining new drugs as transporter substrates, inhibitors, or inducers. Complex models such as spheroids, organoids, and microphysiological systems require standardization and further research with model transporter substrates and inhibitors. In drug discovery, the more traditional transporter assays may be employed as substrate and inhibitor screening assays. In drug development, more complex cell models can be employed in later drug development to better understand how transporter(s) are involved in the absorption, distribution, and excretion of new drugs.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1247-1257"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893218","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 nonhuman primate usage for drug and vaccine evaluation against filoviruses. 非人灵长类动物用于丝状病毒药物和疫苗评估的最新情况。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-10-01 Epub Date: 2024-08-18 DOI: 10.1080/17460441.2024.2386100

Marc-Antoine de La Vega, Ara Xiii, Shane Massey, Jessica R Spengler, Gary P Kobinger, Courtney Woolsey

{"title":"An update on nonhuman primate usage for drug and vaccine evaluation against filoviruses.","authors":"Marc-Antoine de La Vega, Ara Xiii, Shane Massey, Jessica R Spengler, Gary P Kobinger, Courtney Woolsey","doi":"10.1080/17460441.2024.2386100","DOIUrl":"10.1080/17460441.2024.2386100","url":null,"abstract":"Introduction: Due to their faithful recapitulation of human disease, nonhuman primates (NHPs) are considered the gold standard for evaluating drugs against Ebolavirus and other filoviruses. The long-term goal is to reduce the reliance on NHPs with more ethical alternatives. In silico simulations and organoid models have the potential to revolutionize drug testing by providing accurate, human-based systems that mimic disease processes and drug responses without the ethical concerns associated with animal testing. However, as these emerging technologies are still in their developmental infancy, NHP models are presently needed for late-stage evaluation of filovirus vaccines and drugs, as they provide critical insights into the efficacy and safety of new medical countermeasures.Areas covered: In this review, the authors introduce available NHP models and examine the existing literature on drug discovery for all medically significant filoviruses in corresponding models.Expert opinion: A deliberate shift toward animal-free models is desired to align with the 3Rs of animal research. In the short term, the use of NHP models can be refined and reduced by enhancing replicability and publishing negative data. Replacement involves a gradual transition, beginning with the selection and optimization of better small animal models; advancing organoid systems, and using in silico models to accurately predict immunological outcomes.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1185-1211"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11466704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874587","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

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 : 2024-10-01 Epub Date: 2024-07-29 DOI: 10.1080/17460441.2024.2385576

Juan F González, José M Sánchez-Montero

引用次数: 0

Perspectives on current approaches to virtual screening in drug discovery. 透视当前药物发现中的虚拟筛选方法。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-10-01 Epub Date: 2024-08-12 DOI: 10.1080/17460441.2024.2390511

Ingo Muegge, Jörg Bentzien, Yunhui Ge

{"title":"Perspectives on current approaches to virtual screening in drug discovery.","authors":"Ingo Muegge, Jörg Bentzien, Yunhui Ge","doi":"10.1080/17460441.2024.2390511","DOIUrl":"10.1080/17460441.2024.2390511","url":null,"abstract":"Introduction: For the past two decades, virtual screening (VS) has been an efficient hit finding approach for drug discovery. Today, billions of commercially accessible compounds are routinely screened, and many successful examples of VS have been reported. VS methods continue to evolve, including machine learning and physics-based methods.Areas covered: The authors examine recent examples of VS in drug discovery and discuss prospective hit finding results from the critical assessment of computational hit-finding experiments (CACHE) challenge. The authors also highlight the cost considerations and open-source options for conducting VS and examine chemical space coverage and library selections for VS.Expert opinion: The advancement of sophisticated VS approaches, including the use of machine learning techniques and increased computer resources as well as the ease of access to synthetically available chemical spaces, and commercial and open-source VS platforms allow for interrogating ultra-large libraries (ULL) of billions of molecules. An impressive number of prospective ULL VS campaigns have generated potent and structurally novel hits across many target classes. Nonetheless, many successful contemporary VS approaches still use considerably smaller focused libraries. This apparent dichotomy illustrates that VS is best conducted in a fit-for-purpose way choosing an appropriate chemical space. Better methods need to be developed to tackle more challenging targets.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1173-1183"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916442","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

Approaches for the discovery of cinnamic acid derivatives with anticancer potential. 发现具有抗癌潜力的肉桂酸衍生物的方法。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-10-01 Epub Date: 2024-08-06 DOI: 10.1080/17460441.2024.2387122

Ioannis Fotopoulos, Dimitra Hadjipavlou-Litina

{"title":"Approaches for the discovery of cinnamic acid derivatives with anticancer potential.","authors":"Ioannis Fotopoulos, Dimitra Hadjipavlou-Litina","doi":"10.1080/17460441.2024.2387122","DOIUrl":"10.1080/17460441.2024.2387122","url":null,"abstract":"Introduction: Cinnamic acid is a privileged scaffold for the design of biologically active compounds with putative anticancer potential, following different synthetic methodologies and procedures. Since there is a need for the production of potent anticancer, cinnamate moiety can significantly contribute in the design of new and more active anticancer agents.Areas covered: In this review, the authors provide a review on the synthetic approaches for the discovery of cinnamic acid derivatives with anticancer potential. Results from molecular simulations, hybridization, and chemical derivatization along with biological experiments in vitro and structural activity relationships are given, described, and discussed by the authors. Information for the mechanism of action is taken from original literature sources.Expert opinion: The authors suggest that (i) numerous areas of biology-pharmacology need to be considered: selectivity, in vivo studies, toxicity and drug-likeness, the mechanism of action in animals and humans, development of more efficient assays for various cancer types; (ii) hybridization techniques outbalance in the discovery and production of compounds with higher activity and greater selectivity; (iii) repositioning offers new anticancer cinnamic agents.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1281-1291"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893219","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

Molecular dynamics simulations for the structure-based drug design: targeting small-GTPases proteins. 用于基于结构的药物设计的分子动力学模拟：以小型 GTP 酶蛋白为目标。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-10-01 Epub Date: 2024-08-06 DOI: 10.1080/17460441.2024.2387856

Angela Parise, Sofia Cresca, Alessandra Magistrato

{"title":"Molecular dynamics simulations for the structure-based drug design: targeting small-GTPases proteins.","authors":"Angela Parise, Sofia Cresca, Alessandra Magistrato","doi":"10.1080/17460441.2024.2387856","DOIUrl":"10.1080/17460441.2024.2387856","url":null,"abstract":"Introduction: Molecular Dynamics (MD) simulations can support mechanism-based drug design. Indeed, MD simulations by capturing biomolecule motions at finite temperatures can reveal hidden binding sites, accurately predict drug-binding poses, and estimate the thermodynamics and kinetics, crucial information for drug discovery campaigns. Small-Guanosine Triphosphate Phosphohydrolases (GTPases) regulate a cascade of signaling events, that affect most cellular processes. Their deregulation is linked to several diseases, making them appealing drug targets. The broad roles of small-GTPases in cellular processes and the recent approval of a covalent KRas inhibitor as an anticancer agent renewed the interest in targeting small-GTPase with small molecules.Area covered: This review emphasizes the role of MD simulations in elucidating small-GTPase mechanisms, assessing the impact of cancer-related variants, and discovering novel inhibitors.Expert opinion: The application of MD simulations to small-GTPases exemplifies the role of MD simulations in the structure-based drug design process for challenging biomolecular targets. Furthermore, AI and machine learning-enhanced MD simulations, coupled with the upcoming power of quantum computing, are promising instruments to target elusive small-GTPases mutations and splice variants. This powerful synergy will aid in developing innovative therapeutic strategies associated to small-GTPases deregulation, which could potentially be used for personalized therapies and in a tissue-agnostic manner to treat tumors with mutations in small-GTPases.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1259-1279"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893220","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 discovery and development of gefapixant as a novel antitussive therapy. 发现并开发了新型止咳疗法吉非匹克爽。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-10-01 Epub Date: 2024-08-13 DOI: 10.1080/17460441.2024.2391902

Maria Gabriella Matera, Paola Rogliani, Clive P Page, Luigino Calzetta, Mario Cazzola

{"title":"The discovery and development of gefapixant as a novel antitussive therapy.","authors":"Maria Gabriella Matera, Paola Rogliani, Clive P Page, Luigino Calzetta, Mario Cazzola","doi":"10.1080/17460441.2024.2391902","DOIUrl":"10.1080/17460441.2024.2391902","url":null,"abstract":"Introduction: Gefapixant, a P2X 3 receptor antagonist, shows considerable potential in managing refractory or unexplained chronic cough. Clinical trials have consistently demonstrated its efficacy in significantly reducing cough frequency and alleviating associated symptoms. However, its adverse effect profile, particularly taste disturbances such as dysgeusia and hypogeusia, the incidence of which is dose-dependent, poses a significant challenge to patient compliance and overall treatment satisfaction.Areas covered: The authors review the mechanism of action of gefapixant, the dose-dependent nature of its adverse effects and the findings from various clinical trials, including Phase 1, Phase 2, and Phase 3 studies. The authors also cover its regulatory status, post-marketing data, and its main competitors.Expert opinion: Gefapixant represents a significant advancement in treating chronic cough. However, balancing efficacy and tolerability is crucial. Lower effective doses and potential combination therapies may mitigate taste disturbances. Patient education and close monitoring during treatment are also important for optimal outcomes. Further research is needed to refine dosing strategies to minimize side effects while maintaining therapeutic efficacy. This research and personalized treatment approaches are key to optimizing gefapixant therapy, ensuring improved management of chronic cough while reducing adverse effects. However, pharmaceutical trials and proposals must be adapted to align with each regulatory body's specific requirements and concerns.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1159-1172"},"PeriodicalIF":6.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975504","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