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High-throughput screening

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https://www.readbyqxmd.com/read/28647489/a-high-throughput-assay-to-identify-substrate-selective-inhibitors-of-the-erk-protein-kinases
#1
Chad J Miller, Yagmur Muftuoglu, Benjamin E Turk
Extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylate a variety of substrates important for survival and proliferation, and their activity is frequently deregulated in tumors. ERK pathway inhibitors have shown clinical efficacy as anti-cancer drugs, but most patients eventually relapse due to reactivation of the pathway. One factor limiting the efficacy of current therapeutics is the difficulty in reaching clinically effective inhibition of the ERK pathway in the absence of on-target toxicities...
June 21, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28647089/reverse-phase-protein-arrays-elucidate-mechanisms-of-action-and-phenotypic-response-in-2d-and-3d-models
#2
REVIEW
Michael Pawlak, Neil O Carragher
The development of new 2D and 3D phenotypic screening assays combined with high-throughput genomic and proteomic technologies are well placed to advance a new era of molecular pathway informed Phenotypic Drug Discovery. We describe the application of Reverse Phase Protein Array (RPPA) technology to elucidate the mechanism-of-action of small molecules at the post-translational pathway level. We propose that profiling of phenotypic hits and lead molecules in increasingly more complex 3D in vitro and ex vivo models at the post-translational pathway network level represents an effective strategy to both triage and progress the preclinical development of phenotypic screening hits...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28647088/deorphanization-strategies-for-dark-chemical-matter
#3
REVIEW
Anne Mai Wassermann, Matthew Tudor, Meir Glick
The term dark chemical matter (DCM) was recently introduced for those molecules in a screening collection that have never shown any substantial biological activity despite having been tested in hundreds of high-throughput assays. It was suggested that, if hits emerge from this compound pool in future screening campaigns, they should be prioritized due to their exquisite selectivity profile. In this article we define DCM at our company and describe on-going efforts to shed light on the bioactivity of these apparently silent compounds, with an emphasis on multi-parametric profiling methods...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28646586/vaccine-candidate-discovery-for-the-next-generation-of-malaria-vaccines
#4
REVIEW
James Tuju, Gathoni Kamuyu, Linda M Murungi, Faith H A Osier
Although epidemiological observations, IgG passive transfer studies and experimental infections in humans all support the feasibility of developing highly effective malaria vaccines, the precise antigens that induce protective immunity remain uncertain. Here, we review the methodologies applied to vaccine candidate discovery for Plasmodium falciparum malaria from the pre- to post- genomic era. Probing of genomic and/or cDNA libraries with antibodies of defined specificities or functional activity predominated the former, while reverse vaccinology encompassing high throughput in silico analyses of genomic, transcriptomic or proteomic parasite datasets is the mainstay of the latter...
June 24, 2017: Immunology
https://www.readbyqxmd.com/read/28645932/a-functional-nav1-7-navab-chimera-with-a-reconstituted-high-affinity-protx-ii-binding-site
#5
Ramkumar Rajamani, Sophie Wu, Iyoncy Rodrigo, Mian Gao, Simon Low, Lisa Megson, David Wensel, Rick Pieschl, Debra Post-Munson, John Watson, David R Langley, Michael Ahlijanian, Linda Bristow, James Herrington
NaV1.7 is genetically implicated in human pain perception. Rare gain of function mutations in NaV1.7 lead to spontaneous pain in humans whereas loss of function mutations result in congenital insensitivity to pain (CIP). Hence, agents that specifically modulate the function of NaV1.7 have the potential to yield novel therapeutics to treat pain. The complexity of the channel and the challenges to generate recombinant cell lines with high NaV1.7 expression have led to a templated target strategy approach employing chimeras with the bacterial channel, NavAb...
June 23, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28645800/high-throughput-sequencing-of-the-entire-genomic-regions-of-ccm1-krit1-ccm2-and-ccm3-pdcd10-to-search-for-pathogenic-deep-intronic-splice-mutations-in-cerebral-cavernous-malformations
#6
Matthias Rath, Sönke E Jenssen, Konrad Schwefel, Stefanie Spiegler, Dana Kleimeier, Christian Sperling, Lars Kaderali, Ute Felbor
Cerebral cavernous malformations (CCM) are vascular lesions of the central nervous system that can cause headaches, seizures and hemorrhagic stroke. Disease-associated mutations have been identified in three genes: CCM1/KRIT1, CCM2 and CCM3/PDCD10. The precise proportion of deep-intronic variants in these genes and their clinical relevance is yet unknown. Here, a long-range PCR (LR-PCR) approach for target enrichment of the entire genomic regions of the three genes was combined with next generation sequencing (NGS) to screen for coding and non-coding variants...
June 20, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28645753/multi-immunoreaction-based-dual-color-capillary-electrophoresis-for-enhanced-diagnostic-reliability-of-thyroid-gland-disease
#7
Nain Woo, Su-Kang Kim, Seong Ho Kang
Thyroid-stimulating hormone (TSH) secretion plays a critical role in regulating thyroid gland function and circulating thyroid hormones (i.e., thyroxine (T4) and triiodothyronine (T3)). A novel multi-immunoreaction-based dual-color capillary electrophoresis (CE) technique was investigated in this study to assess its reliability in diagnosing thyroid gland disease via simultaneous detection of TSH, T3, and T4 in a single run of CE. Compared to the conventional immunoreaction technique, multi-immunoreaction of biotinylated streptavidin antibodies increased the selectivity and sensitivity for individual hormones in human blood samples...
June 16, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28645106/phorbol-esters-dppa-dpa-promote-furin-expression-involving-transcription-factor-cebp%C3%AE-in-neuronal-cells
#8
Jing-Si Zha, Bing-Lin Zhu, Lu Liu, Yu-Jie Lai, Yan Long, Xiao-Tong Hu, Xiao-Juan Deng, Xue-Feng Wang, Zhen Yan, Guo-Jun Chen
Using high-throughput small molecule screening targeting furin gene, we identified that phorbol esters dPPA (12-Deoxyphorbol 13-phenylacetate 20-acetate) and dPA (12-Deoxyphorbol 13-acetate) significantly increased furin protein and mRNA expression in SH-SY5Y cells. This effect was prevented by PKC (protein kinase C) inhibitor calphostin C but not Ro318220, suggesting that the C1 domain, rather than the catalytic domain of PKC plays an important role. Luciferase assay revealed that nucleotides -7925 to -7426 were sufficient to mediate dPPA/dPA enhancement of furin P1 promoter activity...
June 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28645054/computational-analysis-of-the-toxcast-estrogen-receptor-agonist-assays-to-predict-vitellogenin-induction-by-chemicals-in-male-fish
#9
David A Dreier, Nancy D Denslow, Christopher J Martyniuk
Endocrine disruptors, especially estrogen receptor (ER) agonists, have received considerable research attention. While there are several mechanistic endpoints for ER agonism in the Endocrine Disruptor Screening Program, there have been growing efforts to develop high-throughput screening assays and computational models to reduce testing cost, time, and animal use. For example, there are 16 ER agonist assays and an integrated computational model in ToxCast. In the present study, we examined the relationship between ToxCast ER agonist assays and model activity to male vitellogenin induction in the Fish-Short Term Reproduction Assay...
June 13, 2017: Environmental Toxicology and Pharmacology
https://www.readbyqxmd.com/read/28644734/high-throughput-phenotypic-screening-of-kinase-inhibitors-to-identify-drug-targets-for-polycystic-kidney-disease
#10
Tijmen H Booij, Hester Bange, Wouter N Leonhard, Kuan Yan, Michiel Fokkelman, Steven J Kunnen, Johannes G Dauwerse, Yu Qin, Bob van de Water, Gerard J P van Westen, Dorien J M Peters, Leo S Price
Polycystic kidney disease (PKD) is a prevalent disorder characterized by renal cysts that lead to kidney failure. Various signaling pathways have been targeted to stop disease progression, but most interventions still focus on alleviating PKD-associated symptoms. The mechanistic complexity of the disease, as well as the lack of functional in vitro assays for compound testing, has made drug discovery for PKD challenging. To identify modulators of PKD, Pkd1(-/-) kidney tubule epithelial cells were applied to a scalable and automated 3D cyst culture model for compound screening, followed by phenotypic profiling to determine compound efficacy...
June 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28643453/small-molecule-inhibitors-of-the-tumor-suppressor-fhit
#11
Andreas Marx, Sandra Lange, Stephan Hacker, Philipp Schmid, Martin Scheffner
The tumor suppressor Fhit and its substrate diadenosine triphosphate (Ap3A) are important factors in cancer development and progression. Fhit has Ap3A hydrolase activity and cleaves Ap3A into adenosine monophosphate (AMP) and adenosine diphosphate (ADP) which is believed to terminate Fhit-mediated signaling. How the catalytic activity of Fhit is regulated and how the Fhit-Ap3A complex exerts its growth-suppressive function remain to be discovered. Small molecule inhibitors of the enzymatic activity of Fhit would provide valuable tools for the elucidation of its tumor-suppressive functions...
June 23, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28642766/high-throughput-screening-method-for-identifying-potential-agonists-and-antagonists-of-arabidopsis-thaliana-cytokinin-receptor-cre1-ahk4
#12
Pavel Klimeš, Dušan Turek, Pavel Mazura, Lucia Gallová, Lukáš Spíchal, Břetislav Brzobohatý
The CRE1/AHK4 cytokinin receptor is an important component of plants' hormone signaling systems, and compounds that can alter its activity have potential utility for studying the receptor's functions and/or developing new plant growth regulators. A high throughput method was developed for screening compounds with agonist or antagonist properties toward the CRE1/AHK4 cytokinin receptor in a single experiment using the Nanodrop II liquid handling system and 384-well plates. Potential ligands are screened directly, using a reporter system in which receptor signaling activity triggers expression of β-galactosidase in Escherichia coli...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28642635/virtual-screening-following-rational-drug-design-based-approach-for-introducing-new-anti-amyloid-beta-aggregation-agent
#13
Garshasb Rigi, Mohammad Vala Ashdar Nakhaei, Hoda Eidipour, Arshia Najimi, Fahimeh Tajik, Niloufar Taher, Kamran Yarahmadi
Amyloid β (Aβ) sheets aggregations is the main reason of Alzheimer disease. The interacting areas between monomers are residue number 38 to 42. Inhibition of interaction between Aβ molecules prevents plaque formation. In the present study, we have performed a high-throughput virtual screening among ZINC database and top 1000 hits were checked again regarding binding affinity by AutoDock software. Top 4 successive second step screening hits was considered for drug design purpose against aggregation site of Aβ molecules...
2017: Bioinformation
https://www.readbyqxmd.com/read/28642545/high-throughput-screening-of-small-molecule-inhibitors-of-the-streptococcus-quorum-sensing-signal-pathway
#14
Seiji Ishii, Kenji Fukui, Satoshi Yokoshima, Kazuo Kumagai, Youko Beniyama, Tetsuya Kodama, Tohru Fukuyama, Takayoshi Okabe, Tetsuo Nagano, Hirotatsu Kojima, Takato Yano
The main components of the quorum-sensing system are expected to be favorable targets for drug development to combat various chronic infectious diseases. ComA of Streptococcus is an ATP-binding cassette transporter containing a peptidase domain (PEP), which is essential for the quorum-sensing signal production. Using high-throughput screening, we found a potent small molecule that suppressed the S. mutans quorum-sensing pathway through inhibition of PEP activity. The compound effectively attenuated the biofilm formation and competence development of S...
June 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28640934/substrate-specificity-and-safener-inducibility-of-the-plant-udp-glucose-dependent-family-1-glycosyltransferases-super-family
#15
Melissa Brazier-Hicks, Markus Gershater, David Dixon, Robert Edwards
Plants contain large numbers of family 1 UDP-glucose dependent glycosyltransferases (UGTs), including members that conjugate xenobiotics. Arabidopsis contains 107 UGT genes with 99 family members successfully expressed as glutathione transferase (GST)-fusion proteins in E.coli. A high-throughput catalytic screen was developed based on quantification of the fusion by measuring GST activity. UGT activity using UDP-glucose as donor was then determined using 11 synthetic acceptors bearing hydroxyl, amino and thiol groups that had been shown to undergo conjugation in plant extracts...
June 22, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/28640454/direct-quantification-of-gamma-h2ax-by-cell-based-high-throughput-screening-for-evaluation-of-genotoxicity-of-pesticides-in-a-human-thyroid-cell-lines
#16
Jerome M Hershman, Bryan France, Kevin Hon, Robert Damoiseaux
Genotoxicity is thought to be the cause of many cancers. Genotoxicity due to environmental toxins may be partly responsible for the dramatic increase in the incidence of papillary thyroid cancer over the past two decades. Here, we present a fully automatable assay platform that directly quantifies the phosphorylation of nuclear histone gamma H2AX (γH2AX), a specific cellular marker for DNA double strand breaks (DSBs) via immunohistochemistry and laser scanning cytometry. It multiplexes γH2AX with total cell number measured as propidium iodide and calculates the percentage of cells with DSBs...
June 22, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28640228/development-and-validation-of-a-high-throughput-mass-spectrometry-based-urine-metabolomic-test-for-the-detection-of-colonic-adenomatous-polyps
#17
Lu Deng, David Chang, Rae R Foshaug, Roman Eisner, Victor K Tso, David S Wishart, Richard N Fedorak
Background: Colorectal cancer is one of the leading causes of cancer deaths worldwide. The detection and removal of the precursors to colorectal cancer, adenomatous polyps, is the key for screening. The aim of this study was to develop a clinically scalable (high throughput, low cost, and high sensitivity) mass spectrometry (MS)-based urine metabolomic test for the detection of adenomatous polyps. Methods: Prospective urine and stool samples were collected from 685 participants enrolled in a colorectal cancer screening program to undergo colonoscopy examination...
June 22, 2017: Metabolites
https://www.readbyqxmd.com/read/28639931/contest16s-an-algorithm-that-identifies-contaminated-prokaryotic-genomes-using-16s-rna-gene-sequences
#18
Imchang Lee, Mauricio Chalita, Sung-Min Ha, Seong-In Na, Seok-Hwan Yoon, Jongsik Chun
Thanks to the recent advancement of DNA sequencing technology, the cost and time of prokaryotic genome sequencing have been dramatically decreased. It has repeatedly been reported that genome sequencing using high-throughput next-generation sequencing is prone to contaminations due to its high depth of sequencing coverage. Although a few bioinformatics tools are available to detect potential contaminations, these have inherited limitations as they only use protein-coding genes. Here we introduce a new algorithm, called ContEst16S, to detect potential contaminations using 16S rRNA genes from genome assemblies...
June 22, 2017: International Journal of Systematic and Evolutionary Microbiology
https://www.readbyqxmd.com/read/28639644/differential-detection-and-quantification-of-cyclic-amp-and-other-adenosine-phosphates-in-live-cells
#19
Sujoy Das, Himadri Sekhar Sarkar, Md Raihan Uddin, Kari Rissanen, Sukhendu Mandal, Prithidipa Sahoo
A new naphthol-based rhodamine derivative (NpRD) has been developed for the selective and differential detection of adenosine 3',5'-cyclic monophosphate (cAMP) and adenosine phosphates (APs) (ATP, ADP, and AMP) from other nucleotides. The simple detection and quantification of cAMP in human blood cells and in other samples based on the 'turn on' fluorescence properties of this chemosensor through colorimetry or fluorometry makes it unique for probable application in high throughput screening.
June 22, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28637488/a-high-throughput-colorimetric-assay-for-detection-of-schistosoma-mansoni-viability-based-on-the-tetrazolium-salt-xtt
#20
Pedro Henrique Nascimento Aguiar, Núbia Monteiro Gonçalves Soares Fernandes, Carlos Leomar Zani, Marina Moraes Mourão
BACKGROUND: Schistosoma mansoni is a trematode parasite that causes schistosomiasis, one of the most prevalent neglected tropical diseases, leading to the loss of 2.6 million disability-adjusted life years. Praziquantel is the only drug available, and new drugs are required. The most common strategy in schistosomiasis drug discovery is the use of the schistosomula larval-stage for a pre-screen in drug sensitivity assays. However, assessing schistosomula viability by microscopy has always been a limitation to the throughput of such assays...
June 21, 2017: Parasites & Vectors
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