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High throughput screen

Sheng-Ren Chen, Yi-Yu Ke, Teng-Kuang Yeh, Shu-Yu Lin, Li-Chin Ou, Shu-Chun Chen, Wan-Ting Chang, Hsiao-Fu Chang, Zih-Huei Wu, Chih-Chien Hsieh, Ping-Yee Law, Horace H Loh, Chuan Shih, Yiu-Kay Lai, Shiu-Hwa Yeh, Shau-Hua Ueng
μ-Opioid receptor (MOR) agonists are analgesics used clinically for the treatment of moderate to severe pain, but their use is associated with severe adverse effects such as respiratory depression, constipation, tolerance, dependence, and rewarding effects. In this study, we identified N-({2-[(4-bromo-2-trifluoromethoxyphenyl)sulfonyl]-1,2,3,4-tetrahydro-1-isoquinolinyl}methyl)cyclohexanecarboxamide (1) as a novel opioid receptor agonist by high-throughput screening. Structural modifications made to 1 to improve potency and blood-brain-barrier (BBB) penetration resulted in compounds 45 and 46...
September 20, 2016: European Journal of Medicinal Chemistry
Money Gupta, Rashi Chauhan, Yamuna Prasad, Gulshan Wadhwa, Chakresh Kumar Jain
The lack of complete treatments and appearance of multiple drug-resistance strains of Burkholderia cepacia complex (Bcc) are causing an increased risk of lung infections in cystic fibrosis patients. Bcc infection is a big risk to human health and demands an urgent need to identify new therapeutics against these bacteria. Network biology has emerged as one of the prospective hope in identifying novel drug targets and hits. We have applied protein-protein interaction methodology to identify new drug-target candidates (orthologs) in Burkhloderia cepacia GG4, which is an important strain for studying the quorum-sensing phenomena...
October 8, 2016: Computational Biology and Chemistry
Monika B Dolinska, Nicole Kus, Katie Farney, Paul T Wingfield, Brian P Brooks, Yuri V Sergeev
: Oculocutaneous albinism Type 1 (OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. Two subtypes of OCA1 have been described: severe OCA1A with complete absence of tyrosinase activity and less severe OCA1B with residual tyrosinase activity. Here, we characterize the recombinant human tyrosinase intra-melanosomal domain and mutant variants, which mimic genetic changes in both subtypes of OCA1 patients. Proteins were prepared using site-directed mutagenesis, expressed in insect larvae, purified by chromatography, and characterized by enzymatic activities- tryptophan fluorescence, and Gibbs free energy changes...
October 24, 2016: Pigment Cell & Melanoma Research
Alejandro Parrales, Atul Ranjan, Swathi V Iyer, Subhash Padhye, Scott J Weir, Anuradha Roy, Tomoo Iwakuma
Stabilization of mutant p53 (mutp53) in tumours greatly contributes to malignant progression. However, little is known about the underlying mechanisms and therapeutic approaches to destabilize mutp53. Here, through high-throughput screening we identify statins, cholesterol-lowering drugs, as degradation inducers for conformational or misfolded p53 mutants with minimal effects on wild-type p53 (wtp53) and DNA contact mutants. Statins preferentially suppress mutp53-expressing cancer cell growth. Specific reduction of mevalonate-5-phosphate by statins or mevalonate kinase knockdown induces CHIP ubiquitin ligase-mediated nuclear export, ubiquitylation, and degradation of mutp53 by impairing interaction of mutp53 with DNAJA1, a Hsp40 family member...
October 24, 2016: Nature Cell Biology
Tiago Torres, Isabel Cunha, Rosário Martins, Miguel M Santos
Recently, several emerging pollutants, including Personal Care Products (PCPs), have been detected in aquatic ecosystems, in the ng/L or µg/L range. Available toxicological data is limited, and, for certain PCPs, evidence indicates a potential risk for the environment. Hence, there is an urgent need to gather ecotoxicological data on PCPs as a proxy to improve risk assessment. Here, the toxicity of three different PCPs (4-Methylbenzylidene Camphor (4-MBC), propylparaben and triclocarban) was tested using embryo bioassays with Danio rerio (zebrafish) and Paracentrotus lividus (sea urchin)...
October 21, 2016: International Journal of Molecular Sciences
Liis Andresen, Vallo Varik, Yuzuru Tozawa, Steffi Jimmy, Stina Lindberg, Tanel Tenson, Vasili Hauryliuk
The stringent response is a central adaptation mechanism that allows bacteria to adjust their growth and metabolism according to environmental conditions. The functionality of the stringent response is crucial for bacterial virulence, survival during host invasion as well as antibiotic resistance and tolerance. Therefore, specific inhibitors of the stringent response hold great promise as molecular tools for disarming and pacifying bacterial pathogens. By taking advantage of the valine amino acid auxotrophy of the Bacillus subtilis stringent response-deficient strain, we have set up a High Throughput Screening assay for the identification of stringent response inhibitors...
October 24, 2016: Scientific Reports
Patricia Yuste-Checa, Sandra Brasil, Alejandra Gámez, Jarl Underhaug, Lourdes R Desviat, Magdalena Ugarte, Celia Pérez-Cerdá, Aurora Martinez, Belén Pérez
The congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG), the most common N-glycosylation disorder, is a multisystem disease for which no effective treatment is available. The recent functional characterization of disease-causing mutations described in patients with PMM2-CDG led to the idea of a therapeutic strategy involving pharmacological chaperones (PC) to rescue PMM2 loss-of-function mutations. The present work describes the high-throughput screening, by differential scanning fluorimetry, of 10,000 low molecular weight compounds from a commercial library, to search for possible PCs for the enzyme PMM2...
October 24, 2016: Human Mutation
Zhao Ma, Zhenzhen Liu, Tianyu Jiang, Tianchao Zhang, Huateng Zhang, Lupei Du, Minyong Li
High-throughput screening (HTS) of ligand library to find new active molecules for G protein-coupled receptors is still a major interest, as well as an actual challenge. Fluorescence polarization (FP) assay portrays an essential role in HTS; however, in many cases, it was restricted by the absence of FP probes, the narrow measurement window, and low signal-to-noise (S/N) ratio. Herein, based on the modification of our previous probe 1 (QFL), we discovered an FP probe 3 (QGGFL) for α1-adrenergic receptors (α1-ARs), which has satisfactory fluorescence intensity, specific binding ability to receptors, and suitable fluorescence properties that were compatible with the filters in the FP system...
October 13, 2016: ACS Medicinal Chemistry Letters
Masahiko Terakado, Hidehiro Suzuki, Kazuya Hashimura, Motoyuki Tanaka, Hideyuki Ueda, Hiroshi Kohno, Taku Fujimoto, Hiroshi Saga, Shinji Nakade, Hiromu Habashita, Yoshikazu Takaoka, Takuya Seko
Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA1-6. A high throughput screen against LPA1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH)...
October 13, 2016: ACS Medicinal Chemistry Letters
Chia-Wen Hsu, Jui-Hua Hsieh, Ruili Huang, Dirk Pijnenburg, Thai Khuc, Jon Hamm, Jinghua Zhao, Caitlin Lynch, Rinie van Beuningen, Xiaoqing Chang, Rene Houtman, Menghang Xia
Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3-indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches...
October 20, 2016: Toxicology and Applied Pharmacology
Qiang Sun, Tao Zhou, Jun Niu, Peng Wu, Yanan Guo, Yanfei Yang
The aim of this study was to screen the biomarkers of diabetic limb arterial stenosis. Fasting blood samples of 40 patients with diabetic limb arterial stenosis (experimental group), 40 diabetes patients (diabetic control group), and 40 healthy individuals (healthy control group) were collected. Protein-chip assay analysis and ELISA were used to detect tumor necrosis factor α, interleukin-6, endothelin-1, calcitonin gene-related peptide and high-sensitivity C-reactive protein in the three groups. Protein-chip array analysis and ELISA found consistent results that endothelin-1, tumor necrosis factor α, interleukin-6 and high-sensitivity C-reactive protein in the experimental group were significantly up-regulated while the expression of calcitonin gene-related peptide was down-regulated compared with the healthy control group (P < 0...
October 21, 2016: Vascular
Pan Li, Bin Lv, Xiaoqing Jiang, Ting Wang, Xianghui Ma, Nianwei Chang, Xiaoying Wang, Xiumei Gao
ETHNOPHARMACOLOGICAL RELEVANCE: Shenfu injection (SFI) is a commercial medicinal product approved by the China Food and Drug Administration that is widely used in the treatment of stroke and coronary heart disease. However, the material basis and the mechanism of SFI are not fully understood. AIM OF THE STUDY: With network pharmacology analysis, our research committed to identify the anti-inflammatory ingredients and mechanism of SFI by combining high-throughput screening...
October 19, 2016: Journal of Ethnopharmacology
Stephen R Welch, Lisa Wiggleton Guerrero, Ayan K Chakrabarti, Laura K McMullan, Mike Flint, Gregory R Bluemling, George R Painter, Stuart T Nichol, Christina F Spiropoulou, César G Albariño
Lassa virus (LASV) and Ebola virus (EBOV) infections are important global health issues resulting in significant morbidity and mortality. While several promising drug and vaccine trials for EBOV are ongoing, options for LASV infection are currently limited to ribavirin treatment. A major factor impeding the development of antiviral compounds to treat these infections is the need to manipulate the virus under BSL-4 containment, limiting research to a few institutes worldwide. Here we describe the development of a novel LASV minigenome assay based on the ambisense LASV S segment genome, with authentic terminal untranslated regions flanking a ZsGreen (ZsG) fluorescent reporter protein and a Gaussia princeps luciferase (gLuc) reporter gene...
October 19, 2016: Antiviral Research
Mary E Walter, Alicia Ortiz, Casey Sondgeroth, Nathan M Sindt, Nikolas Duszenko, Jennie L Catlett, You Zhou, Shah Valloppilly, Christopher Anderson, Samodha Fernando, Nicole R Buan
Bacterial and archaeal genomes can contain 30% or more hypothetical genes with no predicted function. Phylogenetically deep-branching microbes, such as methane-producing archaea (methanogens), contain up to 50% genes with unknown function. In order to formulate hypotheses about the function of hypothetical gene functions in the strict anaerobe, Methanosarcina acetivorans, we have developed high-throughput anaerobic techniques to UV mutagenize, screen, and select for mutant strains in 96-well plates. Using these approaches we have isolated 10 mutant strains that exhibit a variety of physiological changes including increased or decreased growth rate relative to the parent strain when cells use methanol and/or acetate as carbon and energy sources...
October 19, 2016: Journal of Microbiological Methods
Margret Thorsteinsdottir, Unnur A Thorsteinsdottir, Finnur F Eiriksson, Hrafnhildur L Runolfsdottir, Inger M Sch Agustsdottir, Steinunn Oddsdottir, Baldur B Sigurdsson, Hordur K Hardarson, Nilesh R Kamble, Snorri Th Sigurdsson, Vidar O Edvardsson, Runolfur Palsson
Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary disorder that leads to excessive urinary excretion of 2,8-dihydroxyadenine (DHA), causing nephrolithiasis and chronic kidney disease. Treatment with allopurinol or febuxostat reduces DHA production and attenuates the renal manifestations. Assessment of DHA crystalluria by urine microscopy is used for therapeutic monitoring, but lacks sensitivity. We report a high-throughput assay based on ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) for quantification of urinary DHA...
September 14, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Huma Siddiqui, Tsute Chen, Ardita Aliko, Piotr M Mydel, Roland Jonsson, Ingar Olsen
BACKGROUND: Reduced salivation is considered a major clinical feature of most but not all cases of primary Sjögren's syndrome (pSS). Reduced saliva flow may lead to changes in the salivary microbiota. These changes have mainly been studied with culture that typically recovers only 65% of the bacteria present. OBJECTIVE: This study was to use high throughput sequencing, covering both cultivated and not-yet-cultivated bacteria, to assess the bacterial microbiota of whole saliva in pSS patients with normal salivation...
2016: Journal of Oral Microbiology
Dimitrios Spiliotopoulos, Amedeo Caflisch
We review the results of fragment-based high-throughput docking to the N-terminal bromodomain of BRD4 and the CREBBP bromodomain. In both docking campaigns the ALTA (anchor-based library tailoring) procedure was used to reduce the size of the initial library by selecting for flexible docking only the molecules that contain a fragment with favorable predicted binding energy. Ranking by a force field-based energy with solvation has resulted in small-molecule hits with low-micromolar affinity and favorable ligand efficiency...
March 2016: Drug Discovery Today. Technologies
Mikael Persson, Jorrit J Hornberg
High content screening enables parallel acquisition of multiple molecular and cellular readouts. In particular the predictive toxicology field has progressed from the advances in high content screening, as more refined end points that report on cellular health can be studied in combination, at the single cell level, and in relatively high throughput. Here, we discuss how high content screening has become an essential tool for Discovery Safety, the discipline that integrates safety and toxicology in the drug discovery process to identify and mitigate safety concerns with the aim to design drug candidates with a superior safety profile...
October 21, 2016: Chemical Research in Toxicology
Beate Schwer, Fahad Khalid, Stewart Shuman
Saccharomyces cerevisiae Dbr1 is a manganese-dependent RNA debranching enzyme that cleaves the 2'-5' phosphodiester bond of the lariat introns formed during pre-mRNA splicing. Dbr1 is a member of the binuclear metallophosphoesterase enzyme superfamily. We showed previously via alanine scanning that RNA debranching in vivo and in vitro depends on conserved active site residues His13, Asp40, Asn85, His86, His179, His231, and His233. Here, by extending the alanine scan, we added Cys11 to the ensemble of essential active site components...
October 7, 2016: RNA
Ying Qiao, Yong Mao, Jun Wang, Ruanni Chen, Yong-Quan Su, Jia Chen, Wei-Qiang Zheng
The white-spot disease caused by marine ciliate Cryptocryon irritans hindered the sustainable development of large yellow croaker Larimichthys crocea industry. Better understandings about the parasite-host interactions in the molecular level will facilitate the prevention of mass mortality of the L. crocea caused by white-spot disease. MicroRNAs (miRNAs) are a class of small RNA molecules about 20-22 nucleotides which post-transcriptionally regulated many protein-coding genes and involved in many biological processes, especially in host-pathogen responses...
October 17, 2016: Fish & Shellfish Immunology
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