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Library Discovery

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https://www.readbyqxmd.com/read/29351497/screen-targeting-lung-and-prostate-cancer-oncogene-identifies-novel-inhibitors-of-rgs17-and-problematic-chemical-substructures
#1
Christopher R Bodle, Josephine H Schamp, Joseph B O'Brien, Michael P Hayes, Meng Wu, Jonathan A Doorn, David L Roman
Regulator of G protein signaling (RGS) proteins temporally regulate heterotrimeric G protein signaling cascades elicited by G protein-coupled receptor activation and thus are essential for cell homeostasis. The dysregulation of RGS protein expression has been linked to several pathologies, spurring discovery efforts to identify small-molecule inhibitors of these proteins. Presented here are the results of a high-throughput screening (HTS) campaign targeting RGS17, an RGS protein reported to be inappropriately upregulated in several cancers...
January 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29349866/amorphous-materials-for-enhanced-localized-surface-plasmon-resonances
#2
Chuanhui Zhu, Qun Xu
The discovery of localized surface plasmon resonances (LSPR) in semiconductor nanocrystals has initiated a new field in plasmonics. And plasmonic nanocrystals of crystal materials have gained rapid development in the past years with a class of materials with unique photoelectronic properties. Present now a growing number of amorphous plasmonic materials are steadily capturing scientific interest of people, though only a few are well-characterized. Here, we focus on the recent development in state-of-the art experiments, and explore the vast library of plasmonic properties in amorphous materials, including their application fields and optical spectral range...
January 19, 2018: Chemistry, An Asian Journal
https://www.readbyqxmd.com/read/29348810/structure-based-virtual-screening-for-the-discovery-of-novel-inhibitors-of-new-delhi-metallo-%C3%AE-lactamase-1
#3
Francesca Spyrakis, Giuseppe Celenza, Francesca Marcoccia, Matteo Santucci, Simon Cross, Pierangelo Bellio, Laura Cendron, Mariagrazia Perilli, Donatella Tondi
Bacterial resistance has become a worldwide concern after the emergence of metallo-β-lactamases (MBLs). They represent one of the major mechanisms of bacterial resistance against beta-lactam antibiotics. Among MBLs, New Delhi metallo-β-lactamase-1 NDM-1, the most prevalent type, is extremely efficient in inactivating nearly all-available antibiotics including last resort carbapenems. No inhibitors for NDM-1 are currently available in therapy, making the spread of NDM-1 producing bacterial strains a serious menace...
January 11, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29347977/expansion-of-cytochrome-p450-and-cathepsin-genes-in-the-generalist-herbivore-brown-marmorated-stink-bug
#4
Raman Bansal, Andy Michel
BACKGROUND: The brown marmorated stink bug (Halyomorpha halys) is an invasive pest in North America which causes severe economic losses on tree fruits, ornamentals, vegetables, and field crops. The H. halys is an extreme generalist and this feeding behaviour may have been a major contributor behind its establishment and successful adaptation in invasive habitats of North America. To develop an understanding into the mechanism of H. halys' generalist herbivory, here we specifically focused on genes putatively facilitating its adaptation on diverse host plants...
January 18, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29343694/sertraline-paroxetine-and-chlorpromazine-are-rapidly-acting-anthelmintic-drugs-capable-of-clinical-repurposing
#5
Janis C Weeks, William M Roberts, Caitlyn Leasure, Brian M Suzuki, Kristin J Robinson, Heather Currey, Phurpa Wangchuk, Ramon M Eichenberger, Aleen D Saxton, Thomas D Bird, Brian C Kraemer, Alex Loukas, John M Hawdon, Conor R Caffrey, Nicole F Liachko
Parasitic helminths infect over 1 billion people worldwide, while current treatments rely on a limited arsenal of drugs. To expedite drug discovery, we screened a small-molecule library of compounds with histories of use in human clinical trials for anthelmintic activity against the soil nematode Caenorhabditis elegans. From this screen, we found that the neuromodulatory drugs sertraline, paroxetine, and chlorpromazine kill C. elegans at multiple life stages including embryos, developing larvae and gravid adults...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29338172/activation-of-nrf2-and-hypoxic-adaptive-response-contribute-to-neuroprotection-elicited-by-phenylhydroxamic-acid-selective-hdac6-inhibitors
#6
Irina N Gaisina, Sue H Lee, Navneet A Kaidery, Manel Ben Aissa, Manuj Ahuja, Natalya N Smirnova, Sushama Wakade, Arsen Gaisin, Megan W Bourassa, Rajiv R Ratan, Sergey V Nikulin, Andrey A Poloznikov, Bobby Thomas, Gregory R J Thatcher, Irina G Gazaryan
Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer's and Parkinson's diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2...
January 17, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29332214/targeted-next-generation-sequencing-in-patients-with-non-syndromic-congenital-heart-disease
#7
Silvia Pulignani, Cecilia Vecoli, Andrea Borghini, Ilenia Foffa, Lamia Ait-Alì, Maria Grazia Andreassi
Congenital heart disease (CHD) is a genetically heterogeneous disease. Targeted next-generation sequencing (NGS) offers a unique opportunity to sequence multiple genes at lower cost and effort compared to Sanger sequencing. We tested a targeted NGS of a specific gene panel in a relatively large population of non-syndromic CHD patients. The patient cohort comprised 68 CHD patients (45 males; 8.3 ± 1.7 years). Amplicon libraries for 16 CHD-strictly related genes were generated using a TruSeq® Custom Amplicon kit (Illumina, CA) and sequenced using the Illumina MiSeq platform...
January 13, 2018: Pediatric Cardiology
https://www.readbyqxmd.com/read/29331148/isolation-of-anti-extra-cellular-vesicle-single-domain-antibodies-by-direct-panning-on-vesicle-enriched-fractions
#8
Milica Popovic, Elisa Mazzega, Barbara Toffoletto, Ario de Marco
BACKGROUND: The thorough understanding of the physiological and pathological processes mediated by extracellular vesicles (EVs) is challenged by purification methods which are cumbersome, not reproducible, or insufficient to yield homogeneous material. Chromatography based on both ion-exchange and immune-capture can represent an effective method to improve EV purification and successive analysis. METHODS: Cell culture supernatant was used as a model sample for assessing the capacity of anion-exchange chromatography to separate distinct EV fractions and to isolate nanobodies by direct panning on whole EVs to recover binders specific for the native conformation of EV-surface epitopes and suitable to develop EV immune-capture reagents...
January 13, 2018: Microbial Cell Factories
https://www.readbyqxmd.com/read/29330364/polypharmacy-through-phage-display-selection-of-glucagon-and-glp-1-receptor-co-agonists-from-a-phage-displayed-peptide-library
#9
Anna Demartis, Armin Lahm, Licia Tomei, Elisa Beghetto, Valentina Di Biasio, Federica Orvieto, Francesco Frattolillo, Paul E Carrington, Sheena Mumick, Brian Hawes, Elisabetta Bianchi, Anandan Palani, Antonello Pessi
A promising emerging area for the treatment of obesity and diabetes is combinatorial hormone therapy, where single-molecule peptides are rationally designed to integrate the complementary actions of multiple endogenous metabolically-related hormones. We describe here a proof-of-concept study on developing unimolecular polypharmacy agents through the use of selection methods based on phage-displayed peptide libraries (PDL). Co-agonists of the glucagon (GCG) and GLP-1 receptors were identified from a PDL sequentially selected on GCGR- and GLP1R-overexpressing cells...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29330361/discovery-of-microrna-target-modules-of-african-rice-oryza-glaberrima-under-salinity-stress
#10
Tapan Kumar Mondal, Alok Kumar Panda, Hukam C Rawal, Tilak Raj Sharma
Oryza glaberrima is the second edible rice in the genus Oryza. It is grown in the African countries. miRNAs are regulatory molecules that are involved in every domains of gene expression including salinity stress response. Although several miRNAs have been reported from various species of Oryza, yet none of them are from this species. Salt treated (200 mM NaCl for 48 h) and control smallRNA libraries of RAM-100, a salt tolerant genotype, each with 2 replications generated 150 conserve and 348 novel miRNAs...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29329659/discovery-of-mcl-1-inhibitors-based-on-a-thiazolidine-2-4-dione-scaffold
#11
Ellis Whiting, Mithun R Raje, Jay Chauhan, Paul T Wilder, Daniel Van Eker, Samuel J Hughes, Nathan G Bowen, Gregory E A Vickers, Ian C Fenimore, Steven Fletcher
Inspired by a rhodanine-based dual inhibitor of Bcl-xL and Mcl-1, a focused library of analogues was prepared wherein the rhodanine core was replaced with a less promiscuous thiazolidine-2,4-dione scaffold. Compounds were initially evaluated for their abilities to inhibit Mcl-1. The most potent compound 12b inhibited Mcl-1 with a Ki of 155 nM. Further investigation revealed comparable inhibition of Bcl-xL (Ki = 90 nM), indicating that the dual inhibitory profile of the initial rhodanine lead had been retained upon switching the heterocycle core...
December 12, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29328995/filter-base-a-web-accessible-chemical-database-for-small-compound-libraries
#12
Baban S Kolte, Sanjay R Londhe, Bhushan R Solanki, Rajesh N Gacche, Rohan J Meshram
Finding novel chemical agents for targeting disease associated drug targets often requires screening of large number of new chemical libraries. In silico methods are generally implemented at initial stages for virtual screening. Filtering of such compound libraries on physicochemical and substructure ground is done to ensure elimination of compounds with undesired chemical properties. Filtering procedure, is redundant, time consuming and requires efficient bioinformatics/computer manpower along with high end software involving huge capital investment that forms a major obstacle in drug discovery projects in academic setup...
January 6, 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29328784/dna-encoded-chemical-libraries-a-selection-system-based-on-endowing-organic-compounds-with-amplifiable-information
#13
Dario Neri, Richard A Lerner
The discovery of organic ligands that bind specifically to proteins is a central problem in chemistry, biology, and the biomedical sciences. The encoding of individual organic molecules with distinctive DNA tags, serving as amplifiable identification bar codes, allows the construction and screening of combinatorial libraries of unprecedented size, thus facilitating the discovery of ligands to many different protein targets. Fundamentally, one links powers of genetics and chemical synthesis. After the initial description of DNA-encoded chemical libraries in 1992, several experimental embodiments of the technology have been reduced to practice...
January 12, 2018: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/29320511/application-of-a-phenotypic-drug-discovery-strategy-to-identify-biological-and-chemical-starting-points-for-inhibition-of-tslp-production-in-lung-epithelial-cells
#14
Adelina Orellana, Vicente García-González, Rosa López, Sonia Pascual-Guiral, Estrella Lozoya, Julia Díaz, Daniel Casals, Antolín Barrena, Stephane Paris, Miriam Andrés, Victor Segarra, Dolors Vilella, Rajneesh Malhotra, Paul Eastwood, Anna Planagumà, Montserrat Miralpeix, Arsenio Nueda
Thymic stromal lymphopoietin (TSLP) is a cytokine released by human lung epithelium in response to external insult. Considered as a master switch in T helper 2 lymphocyte (Th2) mediated responses, TSLP is believed to play a key role in allergic diseases including asthma. The aim of this study was to use a phenotypic approach to identify new biological and chemical starting points for inhibition of TSLP production in human bronchial epithelial cells (NHBE), with the objective of reducing Th2-mediated airway inflammation...
2018: PloS One
https://www.readbyqxmd.com/read/29320403/bacillibactin-and-bacillomycin-analogues-with-cytotoxicities-against-human-cancer-cell-lines-from-marine-bacillus-sp-pku-ma00093-and-pku-ma00092
#15
Mengjie Zhou, Fawang Liu, Xiaoyan Yang, Jing Jin, Xin Dong, Ke-Wu Zeng, Dong Liu, Yingtao Zhang, Ming Ma, Donghui Yang
Nonribosomal peptides from marine Bacillus strains have received considerable attention for their complex structures and potent bioactivities. In this study, we carried out PCR-based genome mining for potential nonribosomal peptides producers from our marine bacterial library. Twenty-one "positive" strains were screened out from 180 marine bacterial strains, and subsequent small-scale fermentation, HPLC and phylogenetic analysis afforded Bacillus sp. PKU-MA00092 and PKU-MA00093 as two candidates for large-scale fermentation and isolation...
January 10, 2018: Marine Drugs
https://www.readbyqxmd.com/read/29319470/coupling-next-generation-sequencing-to-dominant-positive-screens-for-finding-antibiotic-cellular-targets-and-resistance-mechanisms-in-escherichia-coli
#16
Hélène Gingras, Bédis Dridi, Philippe Leprohon, Marc Ouellette
In order to expedite the discovery of genes coding for either drug targets or antibiotic resistance, we have developed a functional genomic strategy termed Plas-Seq. This technique involves coupling a multicopy suppressor library to next-generation sequencing. We generated an Escherichia coli plasmid genomic library that was transformed into E. coli. These transformants were selected step by step using 0.25× to 2× minimum inhibitory concentrations for ceftriaxone, gentamicin, levofloxacin, tetracycline or trimethoprim...
January 10, 2018: Microbial Genomics
https://www.readbyqxmd.com/read/29318563/generation-of-highly-selective-mmp-antibody-inhibitors
#17
Dong Hyun Nam, Xin Ge
Inhibiting individual MMPs of biomedical importance with high selectivity is critical for both fundamental research and therapy development. Here we describe the methods for discovery of inhibitory monoclonal antibodies from synthetic human antibody phage display libraries carrying convex paratopes encoded by long complementarity-determining region (CDR)-H3 segments. We demonstrate the application of this technique for isolation of highly specific and potent antibody inhibitors of human MMP-14.
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29317495/structural-and-mechanistic-analysis-of-a-%C3%AE-glycoside-phosphorylase-identified-by-screening-a-metagenomic-library
#18
Spencer S Macdonald, Ankoor Patel, Veronica L C Larmour, Connor Morgan-Lang, Steven J Hallam, Brian L Mark, Stephen G Withers
Glycoside phosphorylases have considerable potential as catalysts for the assembly of useful glycans for products ranging from functional foods and prebiotics to novel materials. However, the substrate diversity of currently identified phosphorylases is relatively small, limiting their practical applications. To address this limitation, we developed a high-throughput screening approach using the activated substrate 2,4-dinitrophenyl β-D-glucoside (DNPGlc) and inorganic phosphate for identifying glycoside phosphorylase activity and used it to screen a large insert metagenomic library...
January 9, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29316915/a-novel-one-step-approach-for-the-construction-of-yeast-surface-display-fab-antibody-libraries
#19
Simon Rosowski, Stefan Becker, Lars Toleikis, Bernhard Valldorf, Julius Grzeschik, Deniz Demir, Iris Willenbücher, Ramona Gaa, Harald Kolmar, Stefan Zielonka, Simon Krah
BACKGROUND: Yeast surface display (YSD) has proven to be a versatile platform technology for antibody discovery. However, the construction of antibody Fab libraries typically is a tedious three-step process that involves the generation of heavy chain as well as light chain display plasmids in different haploid yeast strains followed by yeast mating. RESULTS: Within this study, we aimed at implementing a focused Golden Gate Cloning approach for the generation of YSD libraries...
January 9, 2018: Microbial Cell Factories
https://www.readbyqxmd.com/read/29316408/agonists-and-antagonists-of-protease-activated-receptor-2-discovered-within-a-dna-encoded-chemical-library-using-mutational-stabilization-of-the-target
#20
Dean G Brown, Giles A Brown, Paolo Centrella, Kaan Certel, Robert M Cooke, John W Cuozzo, Niek Dekker, Christoph E Dumelin, Andrew Ferguson, Cédric Fiez-Vandal, Stefan Geschwindner, Marie-Aude Guié, Sevan Habeshian, Anthony D Keefe, Oliver Schlenker, Eric A Sigel, Arjan Snijder, Holly T Soutter, Linda Sundström, Dawn M Troast, Giselle Wiggins, Jing Zhang, Ying Zhang, Matthew A Clark
The discovery of ligands via affinity-mediated selection of DNA-encoded chemical libraries is driven by the quality and concentration of the protein target. G-protein-coupled receptors (GPCRs) and other membrane-bound targets can be difficult to isolate in their functional state and at high concentrations, and therefore have been challenging for affinity-mediated selection. Here, we report a successful selection campaign against protease-activated receptor 2 (PAR2). Using a thermo-stabilized mutant of PAR2, we conducted affinity selection using our >100-billion-compound DNA-encoded library...
January 1, 2018: SLAS Discovery
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