SLAS Discovery最新文献_第5页

Screening for molecular glues – Challenges and opportunities 分子胶的筛选--挑战与机遇

IF 3.1 4区生物学

SLAS Discovery Pub Date : 2024-03-01 DOI: 10.1016/j.slasd.2023.12.008

Geoffrey A. Holdgate , Catherine Bardelle , Sophia K. Berry , Alice Lanne , Maria Emanuela Cuomo

引用次数: 0

In Memoriam 悼念

IF 3.1 4区生物学

SLAS Discovery Pub Date : 2024-03-01 DOI: 10.1016/j.slasd.2023.05.002

引用次数: 0

Development of a high-throughput screening platform to identify new therapeutic agents for Medulloblastoma Group 3 开发高通量筛选平台，以确定第 3 组髓母细胞瘤的新治疗药物。

IF 3.1 4区生物学

SLAS Discovery Pub Date : 2024-02-12 DOI: 10.1016/j.slasd.2024.100147

Inés Fallon , Henar Hernando , Olga Almacellas-Rabaiget , Berta Marti-Fuster , Cesare Spadoni , Darell D Bigner , Eva Méndez

{"title":"Development of a high-throughput screening platform to identify new therapeutic agents for Medulloblastoma Group 3","authors":"Inés Fallon , Henar Hernando , Olga Almacellas-Rabaiget , Berta Marti-Fuster , Cesare Spadoni , Darell D Bigner , Eva Méndez","doi":"10.1016/j.slasd.2024.100147","DOIUrl":"10.1016/j.slasd.2024.100147","url":null,"abstract":"<div><p>Pediatric brain tumors (PBTs) represent about 25 % of all pediatric cancers and are the most common solid tumors in children and adolescents. Medulloblastoma (MB) is the most frequently occurring malignant PBT, accounting for almost 10 % of all pediatric cancer deaths. MB Group 3 (MB G3) accounts for 25–30 % of all MB cases and has the worst outcome, particularly when associated with MYC amplification. However, no targeted treatments for this group have been developed so far.</p><p>Here we describe a unique high throughput screening (HTS) platform specifically designed to identify new therapies for MB G3. The platform incorporates optimized and validated 2D and 3D efficacy and toxicity models, that account for tumor heterogenicity, limited efficacy and unacceptable toxicity from the very early stage of drug discovery. The platform has been validated by conducting a pilot HTS campaign with a 1280 lead-like compound library. Results showed 8 active compounds, targeting MB reported targets and several are currently approved or in clinical trials for pediatric patients with PBTs, including MB. Moreover, hits were combined to avoid tumor resistance, identifying 3 synergistic pairs, one of which is currently under clinical study for recurrent MB and other PBTs.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555224000091/pdfft?md5=23b3e2054d9f15dc299480ee9099b87f&pid=1-s2.0-S2472555224000091-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139736889","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

The openOCHEM consensus model is the best-performing open-source predictive model in the First EUOS/SLAS joint compound solubility challenge openOCHEM 共识模型是第一届 EUOS/SLAS 联合化合物溶解度挑战赛中表现最佳的开源预测模型

IF 3.1 4区生物学

SLAS Discovery Pub Date : 2024-02-03 DOI: 10.1016/j.slasd.2024.01.005

Andrea Hunklinger , Peter Hartog , Martin Šícho , Guillaume Godin , Igor V. Tetko

{"title":"The openOCHEM consensus model is the best-performing open-source predictive model in the First EUOS/SLAS joint compound solubility challenge","authors":"Andrea Hunklinger , Peter Hartog , Martin Šícho , Guillaume Godin , Igor V. Tetko","doi":"10.1016/j.slasd.2024.01.005","DOIUrl":"10.1016/j.slasd.2024.01.005","url":null,"abstract":"<div><p>The EUOS/SLAS challenge aimed to facilitate the development of reliable algorithms to predict the aqueous solubility of small molecules using experimental data from 100 K compounds. In total, hundred teams took part in the challenge to predict low, medium and highly soluble compounds as measured by the nephelometry assay. This article describes the winning model, which was developed using the publicly available Online CHEmical database and Modeling environment (OCHEM) available on the website <span>https://ochem.eu/article/27</span><svg><path></path></svg>. We describe in detail the assumptions and steps used to select methods, descriptors and strategy which contributed to the winning solution. In particular we show that consensus based on 28 models calculated using descriptor-based and representation learning methods allowed us to obtain the best score, which was higher than those based on individual approaches or consensus models developed using each individual approach. A combination of diverse models allowed us to decrease both bias and variance of individual models and to calculate the highest score. The model based on Transformer CNN contributed the best individual score thus highlighting the power of Natural Language Processing (NLP) methods. The inclusion of information about aleatoric uncertainty would be important to better understand and use the challenge data by the contestants.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555224000066/pdfft?md5=6b7aa512858162a77178db862a6715d1&pid=1-s2.0-S2472555224000066-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139678098","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

Perspectives on phenotypic screening−Screen Design and Assay Technology Special Interest Group 表型筛选视角--筛选设计与检测技术特别兴趣小组

IF 3.1 4区生物学

SLAS Discovery Pub Date : 2024-02-02 DOI: 10.1016/j.slasd.2024.02.001

Chorom Pak , Kaylene J. Simpson , Andrea D. Weston , Mary Ellen Cvijic , Kenda Evans , Andrew D. Napper

{"title":"Perspectives on phenotypic screening−Screen Design and Assay Technology Special Interest Group","authors":"Chorom Pak , Kaylene J. Simpson , Andrea D. Weston , Mary Ellen Cvijic , Kenda Evans , Andrew D. Napper","doi":"10.1016/j.slasd.2024.02.001","DOIUrl":"10.1016/j.slasd.2024.02.001","url":null,"abstract":"<div><p>Here we offer perspectives on phenotypic screening based on a wide-ranging discussion entitled “Phenotypic screening, target ID, and multi-omics: enabling more disease relevance in early discovery?” at the Screen Design and Assay Technology Special Interest Group Meeting at the 2023 SLAS Conference. During the session, the authors shared their own experience from within their respective organizations, followed by an open discussion with the audience. It was recognized that while substantial progress has been made towards translating disease-relevant phenotypic early discovery into clinical success, there remain significant operational and scientific challenges to implementing phenotypic screening efforts, and improving translation of screening hits comes with substantial resource demands and organizational commitment. This Perspective assesses progress, highlights pitfalls, and offers possible solutions to help unlock the therapeutic potential of phenotypic drug discovery. Areas explored comprise screening and hit validation strategy, choice of cellular model, moving beyond 2D cell culture into three dimensions, and leveraging high-dimensional data sets downstream of phenotypic screens.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S247255522400008X/pdfft?md5=6c8f5d753c3f54536e16525d3c3ab6e0&pid=1-s2.0-S247255522400008X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139678102","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

Activity and inhibition of the SARS-CoV-2 Omicron nsp13 R392C variant using RNA duplex unwinding assays 利用 RNA 双链解旋试验分析 SARS-CoV-2 Omicron nsp13 R392C 变体的活性和抑制作用。

IF 3.1 4区生物学

SLAS Discovery Pub Date : 2024-02-01 DOI: 10.1016/j.slasd.2024.01.006

Nicole L. Inniss , Margarita Rzhetskaya , Ted Ling-Hu , Ramon Lorenzo-Redondo , Kelly E. Bachta , Karla J.F. Satchell , Judd F. Hultquist

{"title":"Activity and inhibition of the SARS-CoV-2 Omicron nsp13 R392C variant using RNA duplex unwinding assays","authors":"Nicole L. Inniss , Margarita Rzhetskaya , Ted Ling-Hu , Ramon Lorenzo-Redondo , Kelly E. Bachta , Karla J.F. Satchell , Judd F. Hultquist","doi":"10.1016/j.slasd.2024.01.006","DOIUrl":"10.1016/j.slasd.2024.01.006","url":null,"abstract":"<div><p>SARS-CoV-2 nsp13 helicase is an essential enzyme for viral replication and a promising target for antiviral drug development. This study compares the double-stranded RNA (dsRNA) unwinding activity of nsp13 and the Omicron nsp13<sup>R392C</sup> variant, which is predominant in currently circulating lineages. Using <em>in vitro</em> gel- and fluorescence-based assays, we found that both nsp13 and nsp13<sup>R392C</sup> have dsRNA unwinding activity with equivalent kinetics. Furthermore, the R392C mutation had no effect on the efficiency of the nsp13-specific helicase inhibitor SSYA10-001. We additionally confirmed the activity of several other helicase inhibitors against nsp13, including punicalagin that inhibited dsRNA unwinding at nanomolar concentrations. Overall, this study reveals the utility of using dsRNA unwinding assays to screen small molecules for antiviral activity against nsp13 and the Omicron nsp13<sup>R392C</sup> variant. Continual monitoring of newly emergent variants will be essential for considering resistance profiles of lead compounds as they are advanced towards next-generation therapeutic development.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555224000078/pdfft?md5=f7dc6d1a4af32c1d663782fff14897d5&pid=1-s2.0-S2472555224000078-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139673776","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

3D-Suspension culture platform for high throughput screening of neurotoxic chemicals using LUHMES dopaminergic neurons 利用 LUHMES 多巴胺能神经元高通量筛选神经毒性化学品的三维悬浮培养平台。

IF 3.1 4区生物学

SLAS Discovery Pub Date : 2024-01-26 DOI: 10.1016/j.slasd.2024.01.004

Zhi-Bin Tong, Ruili Huang, John Braisted, Pei-Hsuan Chu, Anton Simeonov, David L. Gerhold

{"title":"3D-Suspension culture platform for high throughput screening of neurotoxic chemicals using LUHMES dopaminergic neurons","authors":"Zhi-Bin Tong, Ruili Huang, John Braisted, Pei-Hsuan Chu, Anton Simeonov, David L. Gerhold","doi":"10.1016/j.slasd.2024.01.004","DOIUrl":"10.1016/j.slasd.2024.01.004","url":null,"abstract":"<div><p>Three-dimensional (3D) cell culture <em>in vitro</em> promises to improve representation of neuron physiology <em>in vivo</em>. This inspired development of a 3D culture platform for LUHMES (Lund Human Mesencephalic) dopaminergic neurons for high-throughput screening (HTS) of chemicals for neurotoxicity. Three culture platforms, adhesion (2D-monolayer), 3D-suspension, and 3D-shaken, were compared to monitor mRNA expression of seven neuronal marker genes, <em>DCX, DRD2, ENO2, NEUROD4, SYN1, TH,</em> and <em>TUBB3</em>. These seven marker genes reached similar maxima in all three formats, with the two 3D platforms showing similar kinetics, whereas several markers peaked earlier in 2D adhesion compared to both 3D culture platforms. The differentiated LUHMES (dLUHMES) neurons treated with ziram, methylmercury or thiram dynamically increased expression of metallothionein biomarker genes <em>MT1G, MT1E</em> and <em>MT2A</em> at 6 h. These gene expression increases were generally more dynamic in 2D adhesion cultures than in 3D cultures, but were generally comparable between 3D-suspension and 3D-u plate (low binding) platforms. Finally, we adapted 3D-suspension culture of dLUHMES and neural stem cells to 1536 well plates with a HTS cytotoxicity assay. This HTS assay revealed that cytotoxicity IC<sub>50</sub> values were not significantly different between adhesion and 3D-suspension platforms for 31 of 34 (91%) neurotoxicants tested, whereas IC<sub>50</sub> values were significantly different for at least two toxicants. In summary, the 3D-suspension culture platform for LUHMES dopaminergic neurons supported full differentiation and reproducible assay results, enabling quantitative HTS (qHTS) for cytotoxicity in 1536 well format with a Robust Z’ score of 0.68.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555224000054/pdfft?md5=6ff5659913d236de92a50d2266c74ac5&pid=1-s2.0-S2472555224000054-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139572293","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

Covalent hits and where to find them 共价键和在哪里可以找到它们？

IF 3.1 4区生物学

SLAS Discovery Pub Date : 2024-01-24 DOI: 10.1016/j.slasd.2024.01.003

Simon C.C. Lucas , J. Henry Blackwell , Sarah H. Hewitt , Hannah Semple , Benjamin C. Whitehurst , Hua Xu

引用次数: 0

Protocol for high throughput 3D drug screening of patient derived melanoma and renal cell carcinoma 患者衍生黑色素瘤和肾细胞癌的高通量三维药物筛选方案

IF 3.1 4区生物学

SLAS Discovery Pub Date : 2024-01-11 DOI: 10.1016/j.slasd.2024.01.002

Luis M. Ortiz Jordan, Virneliz Fernández Vega, Justin Shumate, Adam Peles, Jordan Zeiger, Louis Scampavia, Timothy P. Spicer

{"title":"Protocol for high throughput 3D drug screening of patient derived melanoma and renal cell carcinoma","authors":"Luis M. Ortiz Jordan, Virneliz Fernández Vega, Justin Shumate, Adam Peles, Jordan Zeiger, Louis Scampavia, Timothy P. Spicer","doi":"10.1016/j.slasd.2024.01.002","DOIUrl":"10.1016/j.slasd.2024.01.002","url":null,"abstract":"<div><p>High Throughput Screening (HTS) with 3D cell models is possible thanks to the recent progress and development in 3D cell culture technologies. Results from multiple studies have demonstrated different drug responses between 2D and 3D cell culture. It is now widely accepted that 3D cell models more accurately represent the physiologic conditions of tumors over 2D cell models. However, there is still a need for more accurate tests that are scalable and better imitate the complex conditions in living tissues. Here, we describe ultrahigh throughput 3D methods of drug response profiling in patient derived primary tumors including melanoma as well as renal cell carcinoma that were tested against the NCI oncologic set of FDA approved drugs. We also tested their autologous patient derived cancer associated fibroblasts, varied the <em>in-vitro</em> conditions using matrix vs matrix free methods and completed this in both 3D vs 2D rendered cancer cells. The result indicates a heterologous response to the drugs based on their genetic background, but not on their maintenance condition. Here, we present the methods and supporting results of the HTS efforts using these 3D of organoids derived from patients. This demonstrated the possibility of using patient derived 3D cells for HTS and expands on our screening capabilities for testing other types of cancer using clinically approved anti-cancer agents to find drugs for potential off label use.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555224000029/pdfft?md5=0a92fc4c4df53099e9c90f6f22bf7c70&pid=1-s2.0-S2472555224000029-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139459264","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

Developing recombinant antibodies by phage display technology to neutralize viral infectious diseases 利用噬菌体展示技术开发重组抗体，中和病毒性传染病。

IF 3.1 4区生物学

SLAS Discovery Pub Date : 2024-01-03 DOI: 10.1016/j.slasd.2024.01.001

Mujahed I. Mustafa , Ahmed Mohammed

{"title":"Developing recombinant antibodies by phage display technology to neutralize viral infectious diseases","authors":"Mujahed I. Mustafa , Ahmed Mohammed","doi":"10.1016/j.slasd.2024.01.001","DOIUrl":"10.1016/j.slasd.2024.01.001","url":null,"abstract":"<div><p>The use of recombinant antibodies developed through phage display technology offers a promising approach for combating viral infectious diseases. By specifically targeting antigens on viral surfaces, these antibodies have the potential to reduce the severity of infections or even prevent them altogether. With the emergence of new and more virulent strains of viruses, it is crucial to develop innovative methods to counteract them. Phage display technology has proven successful in generating recombinant antibodies capable of targeting specific viral antigens, thereby providing a powerful tool to fight viral infections. In this mini-review article, we examine the development of these antibodies using phage display technology, and discuss the associated challenges and opportunities in developing novel treatments for viral infectious diseases. Furthermore, we provide an overview of phage display technology. As these methods continue to evolve and improve, novel and sophisticated tools based on phage display and peptide display systems are constantly emerging, offering exciting prospects for solving scientific, medical, and technological problems related to viral infectious diseases in the near future.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555224000017/pdfft?md5=93aed5a9bb73b5e08c82c3d4ec4e0e52&pid=1-s2.0-S2472555224000017-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139106993","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