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Special Issue "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: 15 July 2019

Special Issue Editors

Guest Editor
Dr. Anton Simeonov

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

Department of Chemistry and Biochemistry, University of Delaware, United States
Website | E-Mail
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 papers will be 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 1800 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 (2 papers)

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Research

Open AccessArticle
Improving the Utility of the Tox21 Dataset by Deep Metadata Annotations and Constructing Reusable Benchmarked Chemical Reference Signatures
Molecules 2019, 24(8), 1604; https://doi.org/10.3390/molecules24081604
Received: 20 March 2019 / Revised: 16 April 2019 / Accepted: 19 April 2019 / Published: 23 April 2019
PDF Full-text (5701 KB) | HTML Full-text | XML Full-text | Supplementary Files
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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Open AccessArticle
Identification of Compounds That Inhibit Estrogen-Related Receptor Alpha Signaling Using High-Throughput Screening Assays
Molecules 2019, 24(5), 841; https://doi.org/10.3390/molecules24050841
Received: 25 January 2019 / Revised: 19 February 2019 / Accepted: 23 February 2019 / Published: 27 February 2019
PDF Full-text (7434 KB) | HTML Full-text | XML Full-text | Supplementary Files
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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Figure 1

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Genome-wide microRNA profiling in the sacculus rotundus tissue of rabbit by high-throughput sequencing approach
Author: Shiyi Chen
Affiliation: Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
Email:
Abstract: Rabbit is a widely used animal model for biomedical researches because of the phylogenetic relationship to human beings, short vital cycle, less aggressive behavior and other advantages. However, our basic researches on the genomic biology of rabbit have obviously lagged far behind. The sacculus rotundus is a specific gut-associated lymphoid tissue in rabbit and plays important roles for host immunity. In the present study, we first employed high-throughput sequencing approach to reveal the genome-wide microRNAs among more than 40 rabbits. Our results provide a set of reference microRNAs and hence facilitate the researches on biological implications of microRNAs in rabbit.

Title: Application of NanoBRET Technology to Quantitatively Determine Kinase Inhibitor Potency in Live Cells
Author: Yuren Wang
Affiliation: Reaction Biology Corporation, 1 Great Valley Parkway, Suite 2, Malvern, PA 19355, USA
Email:
Abstract: NanoBRET Technology is a first biophysical technique that broadly enables the quantitative determination of kinase inhibitor occupancy in live cells, without disruption of cellular membrane integrity. This live cell quantitative capability is achieved in live cells via BRET with an optimized set of cell-permeable kinase tracers. As the specificity of the BRET signal is dictated by the placement of NanoLuc on the chosen kinase target, a diverse set of broad-coverage tracers supports a method to profile kinase-specific affinity over a large portion of the kinome. NanoBRETTM TE has enabled the development of live cell quantitative compound binding assays for >200 individual full-length protein kinases, including a key panel of integral membrane kinase receptors. The assays were scaled to 384-well plate format and Z’ analysis demonstrated the assays to be HTS-compatible. Enabled by this new HTS capability, a systematic profiling of dasatinib against kinases was performed in both NanoBRETTM cellular and HotSpot™ biochemical assays. The comparative analysis revealed a surprising intracellular selectivity profile for this drug. IC50 profiling of reference compound panels against Abl1, DDR1 and c-Met were further tested in both assay formats for potency comparison. These results demonstrate high concordance between in vitro biochemical assay (HotSpot™) and cell-based assay (NanoBRETTM). This data strongly suggest the value of assessing live-cell kinase target engagement in parallel with the biochemical tests in kinase lead optimization programs, as the cellular environment may influence potency and selectivity profiles.

Title: Identification of compounds that inhibit estrogen-related receptor alpha (ERRα) signaling using high throughput screening assays
Authors: Menghang Xia1; Christina Teng2
Affiliation: 1 National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland; 2 Division of the National Toxicology Program, Biomolecular Screening Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
Email: [email protected]; [email protected]
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 gamma coactivator 1a (PGC-1α), the PGC/ERR pathway regulates a host of genes which 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 a high throughput screening assay approach, we previously identified several clusters of ERRα agonists in the Tox21 10K library. In the present study, we screened the Tox21 10K compound library using stably transfected HEK293 cells containing either the ERRα-reporter or the reporter plus PGC-1a expression vector. We identified two major groups of antagonist/inhibitor compounds that blocked ERRα activity and/or the PGC/ERR pathway.

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