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Assay and Drug Development Technologies

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https://www.readbyqxmd.com/read/28800248/how-phenotypic-screening-influenced-drug-discovery-lessons-from-five-years-of-practice
#1
Dorothea Haasen, Ulrich Schopfer, Christophe Antczak, Chantale Guy, Florian Fuchs, Paul Selzer
Since 2011, phenotypic screening has been a trend in the pharmaceutical industry as well as in academia. This renaissance was triggered by analyses that suggested that phenotypic screening is a superior strategy to discover first-in-class drugs. Despite these promises and considerable investments, pharmaceutical research organizations have encountered considerable challenges with the approach. Few success stories have emerged in the past 5 years and companies are questioning their investment in this area. In this contribution, we outline what we have learned about success factors and challenges of phenotypic screening...
August 11, 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28800244/exploiting-analysis-of-heterogeneity-to-increase-the-information-content-extracted-from-fluorescence-micrographs-of-transgenic-zebrafish-embryos
#2
Tongying Shun, Albert H Gough, Subramaniam Sanker, Neil A Hukriede, Andreas Vogt
Zebrafish embryos are a near-ideal animal model for drug discovery because of their high genetic and physiological similarity to mammals, small size, high fecundity, and optical transparency. The latter properties make zebrafish at larval stages especially suited for high-content analysis and high throughput screening (HTS). However, inherent biological complexity and the inability to screen multiple specimens in a single well present a challenge for HTS because limiting replicates and high variability often prevent assays from reaching the stringent performance criteria demanded of large-scale screening assays...
August 11, 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28771372/high-content-assay-multiplexing-for-vascular-toxicity-screening-in-induced-pluripotent-stem-cell-derived-endothelial-cells-and-human-umbilical-vein-endothelial-cells
#3
Yasuhiro Iwata, William D Klaren, Connie S Lebakken, Fabian A Grimm, Ivan Rusyn
Endothelial cells (ECs) play a major role in blood vessel formation and function. While there is longstanding evidence for the potential of chemical exposures to adversely affect EC function and vascular development, the hazard potential of chemicals with respect to vascular effects is not routinely evaluated in safety assessments. Induced pluripotent stem cell (iPSC)-derived ECs promise to provide a physiologically relevant, organotypic culture model that is amenable for high-throughput (HT) EC toxicant screening and may represent a viable alternative to traditional in vitro models, including human umbilical vein endothelial cells (HUVECs)...
August 3, 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28742374/high-throughput-analysis-identifying-drugs-that-regulate-apolipoprotein-a-i-synthesis
#4
Michael J Haas, Luisa Onstead-Haas, William Kurban, Harshit Shah, Monica Plazarte, Ayham Chamseddin, Arshag D Mooradian
Apolipoprotein A-I (apo A-I) is the primary antiatherogenic protein in high-density lipoprotein (HDL). Despite the controversy as to the clinical effectiveness of raising HDL, the search is ongoing for safe and effective drugs that increase HDL and apo A-I levels. To identify novel compounds that can increase hepatic apo A-I production, two drug libraries were screened. The NIH clinical collection (NCC) and the NIH clinical collection 2 (NCC2) were purchased from Evotec (San Francisco, CA). The NCC library contains 446 compounds and the NCC2 library contains 281 compounds, all dissolved in dimethylsulfoxide at a concentration of 10 mM...
July 25, 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28604056/literature-search-and-review
#5
Anton Simeonov, Doug Auld
No abstract text is available yet for this article.
June 12, 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28723272/literature-search-and-review
#6
Anton Simeonov, Mindy I Davis, Doug Auld
No abstract text is available yet for this article.
July 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28723271/development-of-three-orthogonal-assays-suitable-for-the-identification-and-qualification-of-pikfyve-inhibitors
#7
Kylie Fogarty, Mohammed Kashem, Andras Bauer, Alexandra Bernardino, Debra Brennan, Brian Cook, Neil Farrow, Teresa Molinaro, Richard Nelson
FYVE-type zinc finger-containing phosphoinositide kinase (PIKfyve) catalyzes the formation of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) from phosphatidylinositol 3-phosphate (PI(3)P). PIKfyve has been implicated in multiple cellular processes, and its role in the regulation of toll-like receptor (TLR) pathways and the production of proinflammatory cytokines has sparked interest in developing small-molecule PIKfyve inhibitors as potential therapeutics to treat autoimmune and inflammatory diseases. We developed three orthogonal assays to identify and qualify small-molecule inhibitors of PIKfyve: (1) a purified component microfluidic enzyme assay that measures the conversion of fluorescently labeled PI(3)P to PI(3,5)P2 by purified recombinant full-length human 6His-PIKfyve (rPIKfyve); (2) an intracellular protein stabilization assay using the kinase domain of PIKfyve expressed in HEK293 cells; and (3) a cell-based functional assay that measures the production of interleukin (IL)-12p70 in human peripheral blood mononuclear cells stimulated with TLR agonists lipopolysaccharide and R848...
July 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28723270/in-the-july-2017-issue-of-assay%C3%A2
#8
Bruce Melancon
No abstract text is available yet for this article.
July 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28723269/identification-of-antipneumococcal-molecules-effective-against-different-streptococcus-pneumoniae-serotypes-using-a-resazurin-based-high-throughput-screen
#9
Hyung Jun Kim, Namyoul Kim, David Shum, Srigouri Huddar, Chul Min Park, Soojin Jang
Streptococcus pneumoniae is a major human pathogen, causing around 1.6 million deaths worldwide each year. By optimizing a resazurin-based assay to detect S. pneumoniae growth in 384-well microplates, we developed a new high-throughput screening (HTS) system for the discovery of antipneumococcal molecules, which was unsuccessful using conventional absorbance measurements. Before applying our protocol to a large-scale screen, we validated the system through a pilot screen targeting about 7,800 bioactive molecules using three different S...
July 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28723268/assay-of-calcium-transients-and-synapses-in-rat-hippocampal-neurons-by-kinetic-image-cytometry-and-high-content-analysis-an-in-vitro-model-system-for-postchemotherapy-cognitive-impairment
#10
Patrick M McDonough, Natalie L Prigozhina, Ranor C B Basa, Jeffrey H Price
Postchemotherapy cognitive impairment (PCCI) is commonly exhibited by cancer patients treated with a variety of chemotherapeutic agents, including the endocrine disruptor tamoxifen (TAM). The etiology of PCCI is poorly understood. Our goal was to develop high-throughput assay methods to test the effects of chemicals on neuronal function applicable to PCCI. Rat hippocampal neurons (RHNs) were plated in 96- or 384-well dishes and exposed to test compounds (forskolin [FSK], 17β-estradiol [ES]), TAM or fulvestrant [FUL], aka ICI 182,780) for 6-14 days...
July 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28631941/analytical-characterization-of-methyl-%C3%AE-cyclodextrin-for-pharmacological-activity-to-reduce-lysosomal-cholesterol-accumulation-in-niemann-pick-disease-type-c1-cells
#11
Rong Li, Jon Hao, Hideji Fujiwara, Miao Xu, Shu Yang, Sheng Dai, Yan Long, Manju Swaroop, Changhui Li, Mylinh Vu, Juan J Marugan, Daniel S Ory, Wei Zheng
Methyl-β-cyclodextrin (MβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease type C1 (NPC1) patient fibroblasts. However, the pharmacological activity of MβCD reported by different laboratories varies. To determine the potential causes of this variation, we analyzed the mass spectrum characteristics, pharmacological activity of three preparations of MβCDs, and the protein expression profiles of NPC1 patient fibroblasts after treatment with different sources of MβCDs. Our data revealed varied mass spectrum profiles and pharmacological activities on the reduction of lysosomal cholesterol accumulation in NPC1 fibroblasts for these three preparations of MβCDs obtained from different batches and different sources...
May 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28631940/moving-forward-with-assay
#12
Bruce Melancon
No abstract text is available yet for this article.
May 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28631939/a-high-throughput-screening-assay-for-nkcc1-cotransporter-using-nonradioactive-rubidium-flux-technology
#13
Sikander Gill, Rajwant Gill, Yang Wen, Thilo Enderle, Doris Roth, Dong Liang
A high-throughput screening (HTS) assay was developed for cotransporter, NKCC1, which is a potential target for the treatment of diverse disorders. This nonradioactive rubidium flux assay coupled with ion channel reader series provides a working screen for this target expressed in human embryonic kidney (HEK) cell line. An eightfold window of detection was achieved with the optimized assay. This new functional assay offered a robust working model for NKCC1 in determining reliable and concordant rank orders of the test compounds supporting its sensitivity and specificity...
May 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28525289/high-throughput-phenotyping-of-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-and-neurons-using-electric-field-stimulation-and-high-speed-fluorescence-imaging
#14
Neil J Daily, Zhong-Wei Du, Tetsuro Wakatsuki
Electrophysiology of excitable cells, including muscle cells and neurons, has been measured by making direct contact with a single cell using a micropipette electrode. To increase the assay throughput, optical devices such as microscopes and microplate readers have been used to analyze electrophysiology of multiple cells. We have established a high-throughput (HTP) analysis of action potentials (APs) in highly enriched motor neurons and cardiomyocytes (CMs) that are differentiated from human induced pluripotent stem cells (iPSCs)...
May 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28426233/investigation-of-classical-organic-and-ionic-liquid-cosolvents-for-early-stage-screening-in-fragment-based-inhibitor-design-with-unrelated-bacterial-and-human-dihydrofolate-reductases
#15
Jacynthe L Toulouse, Sarah M J Abraham, Natalia Kadnikova, Dominic Bastien, Vincent Gauchot, Andreea R Schmitzer, Joelle N Pelletier
Drug design by methods such as fragment screening requires effective solubilization of millimolar concentrations of small organic compounds while maintaining the properties of the biological target. We investigate four organic solvents and three 1-butyl-3-methylimidazolium (BMIm)-based ionic liquids (ILs) as cosolvents to establish conditions for screening two structurally unrelated dihydrofolate reductases (DHFRs) that are prime drug targets. Moderate concentrations (10%-15%) of cosolvents had little effect on inhibition of the microbial type II R67 DHFR and of human DHFR (hDHFR), while higher concentrations of organic cosolvents generally decreased activity of both DHFRs...
April 20, 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28418694/drug-repurposing-patent-applications-october-december-2016
#16
Hermann A M Mucke
No abstract text is available yet for this article.
April 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28418693/validating-the-predicted-effect-of-astemizole-and-ketoconazole-using-a-drosophila-model-of-parkinson-s-disease
#17
Katarzyna Styczyńska-Soczka, Luigi Zechini, Lysimachos Zografos
Parkinson's disease is a growing threat to an ever-ageing population. Despite progress in our understanding of the molecular and cellular mechanisms underlying the disease, all therapeutics currently available only act to improve symptoms and do not stop the disease process. It is therefore imperative that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson's. Drug repurposing has been recognized as being equally as promising as de novo drug discovery in the field of neurodegeneration and Parkinson's disease specifically...
April 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28418692/drug-repurposing-patent-applications-january-march-2017
#18
Hermann A M Mucke
No abstract text is available yet for this article.
April 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28379727/accelerating-precision-drug-development-and-drug-repurposing-by-leveraging-human-genetics
#19
Jill M Pulley, Jana K Shirey-Rice, Robert R Lavieri, Rebecca N Jerome, Nicole M Zaleski, David M Aronoff, Lisa Bastarache, Xinnan Niu, Kenneth J Holroyd, Dan M Roden, Eric P Skaar, Colleen M Niswender, Lawrence J Marnett, Craig W Lindsley, Leeland B Ekstrom, Alan R Bentley, Gordon R Bernard, Charles C Hong, Joshua C Denny
The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples. To ensure these data are used to maximally benefit and accelerate both de novo drug discovery and drug repurposing efforts, we created the Accelerating Drug Development and Repurposing Incubator, a multidisciplinary think tank of experts in various therapeutic areas within both basic and clinical science as well as experts in legal, business, and other operational domains...
April 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28346800/using-chemoinformatics-bioinformatics-and-bioassay-to-predict-and-explain-the-antibacterial-activity-of-nonantibiotic-food-and-drug-administration-drugs
#20
Nour Aldin Kahlous, Muhammad Al Mohdi Bawarish, Muhammad Arabi Sarhan, Manfred Küpper, Ali Hasaba, Mazen Rajab
Discovering of new and effective antibiotics is a major issue facing scientists today. Luckily, the development of computer science offers new methods to overcome this issue. In this study, a set of computer software was used to predict the antibacterial activity of nonantibiotic Food and Drug Administration (FDA)-approved drugs, and to explain their action by possible binding to well-known bacterial protein targets, along with testing their antibacterial activity against Gram-positive and Gram-negative bacteria...
April 2017: Assay and Drug Development Technologies
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