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Molecules
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High Throughput Screening II
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High Throughput Screening II

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (15 July 2019) | Viewed by 14954

Special Issue Editors

Dr. Anton Simeonov

E-Mail Website
Guest Editor
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
Interests: translational research; high-throughput screening; assay development; laboratory automation
Prof. Dr. Zhihao Zhuang

E-Mail Website
Guest Editor
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA
Interests: post-translational modification; ubiquitination; activity-based probes; enzymology; DNA damage tolerance; nucleic acid chemistry; high throughput screening; small molecule inhibitor; cancer, neurodegeneration

Special Issue Information

Dear Colleagues,

In the last decade, we have witnessed the increased popularity of high throughput screening (HTS) in academia for tool compound development and drug discovery. This has been largely fueled by the rapid developments at many fronts of biology, and the novel targets identified through these efforts. The creation of academic screening centers and the NIH Molecular Libraries Roadmap Initiative have spearheaded the effort and provided crucial infrastructural and technical support to many academic labs engaged in probe development and unravelment of fundamental biology using an HTS approach. With the continued growth of the academic drug discovery effort and the increased demands of high quality tool compounds, the interest in HTS will continue to increase among academic researchers. We thus would like to put together this Special Issue on HTS to highlight the most recent development in the many different fronts of HTS research, encompassing novel assay formats, new targets and screening technologies. We invite the submission of full articles and communications reporting recent work on biochemical, cell-based, phenotypic, and targeted screening. We also welcome timely reviews on the above topics and any other areas of HTS that will capture the interest and imagination of the HTS community.

We thank in advance for your contribution to this Special Issue on HTS.

Dr. Anton Simeonov
Prof. Zhihao Zhuang
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • high-throughput screening
  • screening methods
  • screening data analysis
  • novel targets
  • assay artifacts
  • compound profiling
  • assay development
  • cheminformatics
  • laboratory automation

Related Special Issue

Published Papers (4 papers)

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14 pages, 1830 KiB  
Article
Set-Up and Validation of a High Throughput Screening Method for Human Monoacylglycerol Lipase (MAGL) Based on a New Red Fluorescent Probe
by Matteo Miceli, Silvana Casati, Roberta Ottria, Simone Di Leo, Ivano Eberini, Luca Palazzolo, Chiara Parravicini and Pierangela Ciuffreda
Molecules 2019, 24(12), 2241; https://doi.org/10.3390/molecules24122241 - 15 Jun 2019
Cited by 9 | Viewed by 3667
Abstract
Monoacylglycerol lipase (MAGL) is a serine hydrolase that has a key regulatory role in controlling the levels of 2-arachidonoylglycerol (2-AG), the main signaling molecule in the endocannabinoid system. Identification of selective modulators of MAGL enables both to provide new tools for investigating pathophysiological [...] Read more.
Monoacylglycerol lipase (MAGL) is a serine hydrolase that has a key regulatory role in controlling the levels of 2-arachidonoylglycerol (2-AG), the main signaling molecule in the endocannabinoid system. Identification of selective modulators of MAGL enables both to provide new tools for investigating pathophysiological roles of 2-AG, and to discover new lead compounds for drug design. The development of sensitive and reliable methods is crucial to evaluate this modulatory activity. In the current study, we report readily synthesized long-wavelength putative fluorogenic substrates with different acylic side chains to find a new probe for MAGL activity. 7-Hydroxyresorufinyl octanoate proved to be the best substrate thanks to the highest rate of hydrolysis and the best Km and Vmax values. In addition, in silico evaluation of substrates interaction with the active site of MAGL confirms octanoate resorufine derivative as the molecule of choice. The well-known MAGL inhibitors URB602 and methyl arachidonylfluorophosphonate (MAFP) were used for the assay validation. The assay was highly reproducible with an overall average Z′ value of 0.86. The fast, sensitive and accurate method described in this study is suitable for low-cost high-throughput screening (HTS) of MAGL modulators and is a powerful new tool for studying MAGL activity. Full article
(This article belongs to the Special Issue High Throughput Screening II)
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19 pages, 5701 KiB  
Article
Improving the Utility of the Tox21 Dataset by Deep Metadata Annotations and Constructing Reusable Benchmarked Chemical Reference Signatures
by Daniel J. Cooper and Stephan Schürer
Molecules 2019, 24(8), 1604; https://doi.org/10.3390/molecules24081604 - 23 Apr 2019
Cited by 3 | Viewed by 3626
Abstract
The Toxicology in the 21st Century (Tox21) project seeks to develop and test methods for high-throughput examination of the effect certain chemical compounds have on biological systems. Although primary and toxicity assay data were readily available for multiple reporter gene modified cell lines, [...] Read more.
The Toxicology in the 21st Century (Tox21) project seeks to develop and test methods for high-throughput examination of the effect certain chemical compounds have on biological systems. Although primary and toxicity assay data were readily available for multiple reporter gene modified cell lines, extensive annotation and curation was required to improve these datasets with respect to how FAIR (Findable, Accessible, Interoperable, and Reusable) they are. In this study, we fully annotated the Tox21 published data with relevant and accepted controlled vocabularies. After removing unreliable data points, we aggregated the results and created three sets of signatures reflecting activity in the reporter gene assays, cytotoxicity, and selective reporter gene activity, respectively. We benchmarked these signatures using the chemical structures of the tested compounds and obtained generally high receiver operating characteristic (ROC) scores, suggesting good quality and utility of these signatures and the underlying data. We analyzed the results to identify promiscuous individual compounds and chemotypes for the three signature categories and interpreted the results to illustrate the utility and re-usability of the datasets. With this study, we aimed to demonstrate the importance of data standards in reporting screening results and high-quality annotations to enable re-use and interpretation of these data. To improve the data with respect to all FAIR criteria, all assay annotations, cleaned and aggregate datasets, and signatures were made available as standardized dataset packages (Aggregated Tox21 bioactivity data, 2019). Full article
(This article belongs to the Special Issue High Throughput Screening II)
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25 pages, 7434 KiB  
Article
Identification of Compounds That Inhibit Estrogen-Related Receptor Alpha Signaling Using High-Throughput Screening Assays
by Caitlin Lynch, Jinghua Zhao, Srilatha Sakamuru, Li Zhang, Ruili Huang, Kristine L. Witt, B. Alex Merrick, Christina T. Teng and Menghang Xia
Molecules 2019, 24(5), 841; https://doi.org/10.3390/molecules24050841 - 27 Feb 2019
Cited by 15 | Viewed by 3500
Abstract
The nuclear receptor, estrogen-related receptor alpha (ERRα; NR3B1), plays a pivotal role in energy homeostasis. Its expression fluctuates with the demands of energy production in various tissues. When paired with the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), the PGC/ERR pathway regulates a [...] Read more.
The nuclear receptor, estrogen-related receptor alpha (ERRα; NR3B1), plays a pivotal role in energy homeostasis. Its expression fluctuates with the demands of energy production in various tissues. When paired with the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), the PGC/ERR pathway regulates a host of genes that participate in metabolic signaling networks and in mitochondrial oxidative respiration. Unregulated overexpression of ERRα is found in many cancer cells, implicating a role in cancer progression and other metabolism-related diseases. Using high throughput screening assays, we screened the Tox21 10K compound library in stably transfected HEK293 cells containing either the ERRα-reporter or the reporter plus PGC-1α expression plasmid. We identified two groups of antagonists that were potent inhibitors of ERRα activity and/or the PGC/ERR pathway: nine antineoplastic agents and thirteen pesticides. Results were confirmed using gene expression studies. These findings suggest a novel mechanism of action on bioenergetics for five of the nine antineoplastic drugs. Nine of the thirteen pesticides, which have not been investigated previously for ERRα disrupting activity, were classified as such. In conclusion, we demonstrated that high-throughput screening assays can be used to reveal new biological properties of therapeutic and environmental chemicals, broadening our understanding of their modes of action. Full article
(This article belongs to the Special Issue High Throughput Screening II)
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11 pages, 2006 KiB  
Technical Note
A High Throughput Apoptosis Assay using 3D Cultured Cells
by Sang-Yun Lee, Il Doh and Dong Woo Lee
Molecules 2019, 24(18), 3362; https://doi.org/10.3390/molecules24183362 - 16 Sep 2019
Cited by 10 | Viewed by 3686
Abstract
A high throughput apoptosis assay using 3D cultured cells was developed with a micropillar/microwell chip platform. Live cell apoptosis assays based on fluorescence detection have been useful in high content screening. To check the autofluorescence of drugs, controls (no caspase-3/7 reagent in the [...] Read more.
A high throughput apoptosis assay using 3D cultured cells was developed with a micropillar/microwell chip platform. Live cell apoptosis assays based on fluorescence detection have been useful in high content screening. To check the autofluorescence of drugs, controls (no caspase-3/7 reagent in the assay) for the drugs are necessary which require twice the test space. Thus, a high throughput capability and highly miniaturized format for reducing reagent usage are necessary in live cell apoptosis assays. Especially, the expensive caspase-3/7 reagent should be reduced in a high throughput screening system. To solve this issue, we developed a miniaturized apoptosis assay using micropillar/microwell chips for which we tested seventy drugs (six replicates) per chip and reduced the assay volume to 1 µL. This reduced assay volume can decrease the assay costs compared to the 10–40 µL assay volumes used in 384 well plates. In our experiments, among the seventy drugs, four drugs (Cediranib, Cabozatinib, Panobinostat, and Carfilzomib) induced cell death by apoptosis. Those results were confirmed with western blot assays and proved that the chip platform could be used to identify high potency apoptosis-inducing drugs in 3D cultured cells with alginate. Full article
(This article belongs to the Special Issue High Throughput Screening II)
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