SLAS Discovery最新文献_第3页

Structure-activity relationships of thiadiazole agonists of the human secretin receptor 人类胰泌素受体噻二唑激动剂的结构-活性关系。

IF 2.7 4区生物学

SLAS Discovery Pub Date : 2024-08-08 DOI: 10.1016/j.slasd.2024.100176

Robert Ardecky , Daniela G. Dengler , Kaleeckal G. Harikumar , Mathew M. Abelman , Jiwen Zou , Bryan A. Kramer , Santhi Reddy Ganji , Steve Olson , Alina Ly , Nikhil Puvvula , Chen-Ting Ma , Raghuveer Ramachandra , Eduard A. Sergienko , Laurence J. Miller

{"title":"Structure-activity relationships of thiadiazole agonists of the human secretin receptor","authors":"Robert Ardecky , Daniela G. Dengler , Kaleeckal G. Harikumar , Mathew M. Abelman , Jiwen Zou , Bryan A. Kramer , Santhi Reddy Ganji , Steve Olson , Alina Ly , Nikhil Puvvula , Chen-Ting Ma , Raghuveer Ramachandra , Eduard A. Sergienko , Laurence J. Miller","doi":"10.1016/j.slasd.2024.100176","DOIUrl":"10.1016/j.slasd.2024.100176","url":null,"abstract":"<div><p>Agonists of the secretin receptor have potential applications for diseases of the cardiovascular, gastrointestinal, and metabolic systems, yet no clinically-active non-peptidyl agonists of this receptor have yet been developed. In the current work, we have identified a new small molecule lead compound with this pharmacological profile. We have prepared and characterized a systematic structure-activity series around this thiadiazole scaffold to better understand the molecular determinants of its activity. We were able to enhance the <em>in vitro</em> activity and to maintain the specificity of the parent compound. We found the most active candidate to be quite stable in plasma, although it was metabolized by hepatic microsomes. This chemical probe should be useful for <em>in vitro</em> studies and needs to be tested for <em>in vivo</em> pharmacological activity. This could be an important lead toward the development of a first-in-class orally active agonist of the secretin receptor, which could be useful for multiple disease states.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 6","pages":"Article 100176"},"PeriodicalIF":2.7,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555224000388/pdfft?md5=237988fb6dfd70241f35deecdd6ffa90&pid=1-s2.0-S2472555224000388-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Application of FRET- and BRET-based live-cell biosensors in deorphanization and ligand discovery studies on orphan G protein-coupled receptors 基于 FRET 和 BRET 的活细胞生物传感器在孤儿 G 蛋白偶联受体去形态化和配体发现研究中的应用。

IF 2.7 4区生物学

SLAS Discovery Pub Date : 2024-07-29 DOI: 10.1016/j.slasd.2024.100174

Joanna J. Sajkowska , Choi Har Tsang , Paweł Kozielewicz

引用次数: 0

A high-throughput response to the SARS-CoV-2 pandemic 高通量应对 SARS-CoV-2 大流行

IF 2.7 4区生物学

SLAS Discovery Pub Date : 2024-07-01 DOI: 10.1016/j.slasd.2024.100160

引用次数: 0

High-throughput kinetics in drug discovery 药物发现中的高通量动力学。

IF 2.7 4区生物学

SLAS Discovery Pub Date : 2024-07-01 DOI: 10.1016/j.slasd.2024.100170

Maria Filipa Pinto , Julija Sirina , Nicholas D Holliday , Claire L McWhirter

引用次数: 0

Development of a NanoBRET assay for evaluation of 14-3-3σ molecular glues 开发用于评估 14-3-3σ 分子胶的 NanoBRET 分析法。

IF 2.7 4区生物学

SLAS Discovery Pub Date : 2024-07-01 DOI: 10.1016/j.slasd.2024.100165

Holly R. Vickery , Johanna M. Virta , Markella Konstantinidou, Michelle R. Arkin

{"title":"Development of a NanoBRET assay for evaluation of 14-3-3σ molecular glues","authors":"Holly R. Vickery , Johanna M. Virta , Markella Konstantinidou, Michelle R. Arkin","doi":"10.1016/j.slasd.2024.100165","DOIUrl":"10.1016/j.slasd.2024.100165","url":null,"abstract":"<div><p>We report the development of a 384-well formatted NanoBRET assay to characterize molecular glues of 14-3-3/client interactions in living cells. The seven isoforms of 14-3-3 are dimeric hub proteins with diverse roles including transcription factor regulation and signal transduction. 14-3-3 interacts with hundreds of client proteins to regulate their function and is therefore an ideal therapeutic target when client selectivity can be achieved. We have developed the NanoBRET system for three 14-3-3σ client proteins CRAF, TAZ, and estrogen receptor α (ERα), which represent three specific binding modes. We have measured stabilization of 14-3-3σ/client complexes by molecular glues with EC<sub>50</sub> values between 100 nM and 1 μM in cells, which align with the EC<sub>50</sub> values calculated by fluorescence anisotropy in vitro. Developing this NanoBRET system for the hub protein 14-3-3σ allows for a streamlined approach, bypassing multiple optimization steps in the assay development process for other 14-3-3σ clients. The NanoBRET system allows for an assessment of PPI stabilization in a more physiologically relevant, cell-based environment using full-length proteins. The method is applicable to diverse protein-protein interactions (PPIs) and offers a robust platform to explore libraries of compounds for both PPI stabilizers and inhibitors.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 5","pages":"Article 100165"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555224000273/pdfft?md5=e9c66b542a3d17a9f5d1ab45060e1740&pid=1-s2.0-S2472555224000273-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141155812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to “Automation of high-throughput mRNA-seq library preparation: a robust, hands-free and time efficient methodology” [SLAS Discovery, Volume 27 (2022) P140-147/2472-5552] 对 "高通量 mRNA-seq 文库制备自动化：一种稳健、无需动手且省时的方法"[《SLAS Discovery》，第 27 卷（2022 年）P140-147/2472-5552]的更正。

IF 2.7 4区生物学

SLAS Discovery Pub Date : 2024-07-01 DOI: 10.1016/j.slasd.2024.100169

引用次数: 0

Profiling cells with DELs: Small molecule fingerprinting of cell surfaces 用 DELs 分析细胞：细胞表面的小分子指纹图谱

IF 2.7 4区生物学

SLAS Discovery Pub Date : 2024-07-01 DOI: 10.1016/j.slasd.2024.100171

Jason Deng , Svetlana Belyanskaya, Ninad Prabhu , Christopher Arico-Muendel, Hongfeng Deng , Christopher B. Phelps , David I. Israel , Hongfang Yang , Joseph Boyer , G. Joseph Franklin , Jeremy L. Yap , Kenneth E. Lind , Ching-Hsuan Tsai , Christine Donahue , Jennifer D. Summerfield

{"title":"Profiling cells with DELs: Small molecule fingerprinting of cell surfaces","authors":"Jason Deng , Svetlana Belyanskaya, Ninad Prabhu , Christopher Arico-Muendel, Hongfeng Deng , Christopher B. Phelps , David I. Israel , Hongfang Yang , Joseph Boyer , G. Joseph Franklin , Jeremy L. Yap , Kenneth E. Lind , Ching-Hsuan Tsai , Christine Donahue , Jennifer D. Summerfield","doi":"10.1016/j.slasd.2024.100171","DOIUrl":"10.1016/j.slasd.2024.100171","url":null,"abstract":"<div><p>DNA-encoded small molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, it has been used to identify ligands against targets that are soluble or overexpressed on cell surfaces. Here, we report applying cell-based selection methods to profile surfaces of mouse C2C12 myoblasts and myotube cells in an unbiased, target agnostic manner. A panel of on-DNA compounds were identified and confirmed for cell binding selectivity. We optimized the cell selection protocol and employed a novel data analysis method to identify cell selective ligands against a panel of human B and T lymphocytes. We discuss the generality of using this workflow for DNA encoded small molecule library selection and data analysis against different cell types, and the feasibility of applying this method to profile cell surfaces for biomarker and target identification.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 5","pages":"Article 100171"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555224000339/pdfft?md5=c0f34f61b83c77e23483474ae6a68680&pid=1-s2.0-S2472555224000339-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141452411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A robust CETSA data analysis automation workflow for routine screening 用于常规筛查的强大 CETSA 数据分析自动化工作流程。

IF 2.7 4区生物学

SLAS Discovery Pub Date : 2024-07-01 DOI: 10.1016/j.slasd.2024.100172

引用次数: 0

A high-throughput cell-based screening method for Zika virus protease inhibitor discovery 基于细胞的高通量寨卡病毒蛋白酶抑制剂筛选方法

IF 2.7 4区生物学

SLAS Discovery Pub Date : 2024-07-01 DOI: 10.1016/j.slasd.2024.100164

{"title":"A high-throughput cell-based screening method for Zika virus protease inhibitor discovery","authors":"","doi":"10.1016/j.slasd.2024.100164","DOIUrl":"10.1016/j.slasd.2024.100164","url":null,"abstract":"<div><p>Zika virus (ZIKV) continues to pose a significant global public health threat, with recurring regional outbreaks and potential for pandemic spread. Despite often being asymptomatic, ZIKV infections can have severe consequences, including neurological disorders and congenital abnormalities. Unfortunately, there are currently no approved vaccines or antiviral drugs for the prevention or treatment of ZIKV. One promising target for drug development is the ZIKV NS2B-NS3 protease due to its crucial role in the virus life cycle. In this study, we established a cell-based ZIKV protease inhibition assay designed for high-throughput screening (HTS). Our assay relies on the ZIKV protease's ability to cleave a cyclised firefly luciferase fused to a natural cleavage sequence between NS2B and NS3 protease within living cells. We evaluated the performance of our assay in HTS setting using the pharmacologic controls (JNJ-40418677 and MK-591) and by screening a Library of Pharmacologically Active Compounds (LOPAC). The results confirmed the feasibility of our assay for compound library screening to identify potential ZIKV protease inhibitors.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 5","pages":"Article 100164"},"PeriodicalIF":2.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555224000261/pdfft?md5=bf5f1d749131f99bf6ee476dc8d7194b&pid=1-s2.0-S2472555224000261-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141136693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Compound management in a virtual research organization: The cornerstone of a reliable MMV discovery engine 虚拟研究机构中的化合物管理：可靠的 MMV 发现引擎的基石。

IF 3.1 4区生物学

SLAS Discovery Pub Date : 2024-06-10 DOI: 10.1016/j.slasd.2024.100168

Anna Adam, Elodie Chenu, Dominique Besson

{"title":"Compound management in a virtual research organization: The cornerstone of a reliable MMV discovery engine","authors":"Anna Adam, Elodie Chenu, Dominique Besson","doi":"10.1016/j.slasd.2024.100168","DOIUrl":"10.1016/j.slasd.2024.100168","url":null,"abstract":"<div><p>Despite the efforts towards malaria eradication, latest estimates show that the number of malaria cases is still rising, and malaria continues to have a devastating impact on people's health and livelihoods particularly in populations located in sub-Saharan Africa <sup>1</sup>. As a Product Development Partnership (PDP), MMV Medicines for Malaria Venture (MMV) plays a crucial role by using public and philanthropic funds to engage the pharmaceutical industry and academic research institutions to discover, develop and deliver the new drugs needed to control and eradicate malaria. MMV Discovery, working with partners, has developed a robust pipeline of molecules and a reliable discovery engine able to support research projects from screening to candidate nomination, providing access to centers of expertise and evaluating the profile and potential of molecules. To efficiently support this malaria discovery effort, MMV and its partners have established a state-of-the-art compound management network, supporting all discovery activities. This network serves both discovery projects and open innovation initiatives, such as MMV Open, tailoring workflows to align with distinct project objectives. In addition to this, MMV has implemented reliable integrated logistic tools and interfaces. These tools enable the efficient management and tracking of individual not solubilized (dry) samples of project compounds, as well as dedicated, solubilized libraries of compounds designated for primary screens targeting malaria and other neglected diseases.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 5","pages":"Article 100168"},"PeriodicalIF":3.1,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555224000303/pdfft?md5=938ea9a32dbd6548b3ddd7c3c0aacd0c&pid=1-s2.0-S2472555224000303-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141312508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0