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Library Discovery

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https://www.readbyqxmd.com/read/27932801/dna-encoded-chemistry-enabling-the-deeper-sampling-of-chemical-space
#1
Robert A Goodnow, Christoph E Dumelin, Anthony D Keefe
DNA-encoded chemical library technologies are increasingly being adopted in drug discovery for hit and lead generation. DNA-encoded chemistry enables the exploration of chemical spaces four to five orders of magnitude more deeply than is achievable by traditional high-throughput screening methods. Operation of this technology requires developing a range of capabilities including aqueous synthetic chemistry, building block acquisition, oligonucleotide conjugation, large-scale molecular biological transformations, selection methodologies, PCR, sequencing, sequence data analysis and the analysis of large chemistry spaces...
December 9, 2016: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/27927161/scifio-an-extensible-framework-to-support-scientific-image-formats
#2
Mark C Hiner, Curtis T Rueden, Kevin W Eliceiri
BACKGROUND: No gold standard exists in the world of scientific image acquisition; a proliferation of instruments each with its own proprietary data format has made out-of-the-box sharing of that data nearly impossible. In the field of light microscopy, the Bio-Formats library was designed to translate such proprietary data formats to a common, open-source schema, enabling sharing and reproduction of scientific results. While Bio-Formats has proved successful for microscopy images, the greater scientific community was lacking a domain-independent framework for format translation...
December 7, 2016: BMC Bioinformatics
https://www.readbyqxmd.com/read/27924586/rna-sequencing-analysis-of-salivary-extracellular-rna
#3
Blanca Majem, Feng Li, Jie Sun, David T W Wong
Salivary biomarkers for disease detection, diagnostic and prognostic assessments have become increasingly well established in recent years. In this chapter we explain the current leading technology that has been used to characterize salivary non-coding RNAs (ncRNAs) from the extracellular RNA (exRNA) fraction: HiSeq from Illumina® platform for RNA sequencing. Therefore, the chapter is divided into two main sections regarding the type of the library constructed (small and long ncRNA libraries), from saliva collection, RNA extraction and quantification to cDNA library generation and corresponding QCs...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27917874/discovery-synthesis-biological-evaluation-and-structure-based-optimization-of-novel-piperidine-derivatives-as-acetylcholine-binding-protein-ligands
#4
Jian Shen, Xi-Cheng Yang, Ming-Cheng Yu, Li Xiao, Xun-Jie Zhang, Hui-Jiao Sun, Hao Chen, Guan-Xin Pan, Yu-Rong Yan, Si-Chen Wang, Wei Li, Lu Zhou, Qiong Xie, Lin-Qian Yu, Yong-Hui Wang, Li-Ming Shao
The homomeric α7 nicotinic receptor (α7 nAChR) is widely expressed in the human brain that could be activated to suppress neuroinflammation, oxidative stress and neuropathic pain. Consequently, a number of α7 nAChR agonists have entered clinical trials as anti-Alzheimer's or anti-psychotic therapies. However, high-resolution crystal structure of the full-length α7 receptor is thus far unavailable. Since acetylcholine-binding protein (AChBP) from Lymnaea stagnalis is most closely related to the α-subunit of nAChRs, it has been used as a template for the N-terminal domain of α-subunit of nAChR to study the molecular recognition process of nAChR-ligand interactions, and to identify ligands with potential nAChR-like activities...
December 5, 2016: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/27917820/a-simple-method-for-producing-multiple-copies-of-controlled-release-small-molecule-microarrays-for-cell-based-screening
#5
Satoshi Fujita, Reiko Onuki-Nagasaki, Kenjiro Ikuta, Yusuke Hara
Traditional drug discovery involves the screening of lead compounds from a chemical library by using cell-based high throughput screening (HTS) procedures. This has created a demand for the development of cell-based microarray chips for HTS of compounds. Although several cell-based microarray devices and procedures for screening of chemical libraries have been reported, each has limitations in terms of simplicity, speed, and cost. Here, we sought to make a simple method for producing multiple copies of microarray chips for the controlled release of small molecules during cell-based screening...
December 5, 2016: Biofabrication
https://www.readbyqxmd.com/read/27915192/the-profiling-of-the-metabolites-of-hirsutine-in-rat-by-ultra-high-performance-liquid-chromatography-coupled-with-linear-ion-trap-orbitrap-mass-spectrometry-an-improved-strategy-for-the-systematic-screening-and-identification-of-metabolites-in-multi-samples
#6
Jianwei Wang, Peng Qi, Jinjun Hou, Yao Shen, Min Yang, Qirui Bi, Yanping Deng, Xiaojian Shi, Ruihong Feng, Zijin Feng, Wanying Wu, Dean Guo
Drug metabolites identification and construction of metabolic profile are meaningful work for the drug discovery and development. The great challenge during this process is the work of the structural clarification of possible metabolites in the complicated biological matrix, which often resulting in a huge amount data sets, especially in multi-samples in vivo. Analyzing these complex data manually is time-consuming and laborious. The object of this study was to develop a practical strategy for screening and identifying of metabolites from multiple biological samples efficiently...
November 21, 2016: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/27914361/development-of-cxcr4-modulators-by-virtual-hts-of-a-novel-amide-sulfamide-compound-library
#7
Renren Bai, Qi Shi, Zhongxing Liang, Younghyoun Yoon, Yiran Han, Amber Feng, Shuangping Liu, Yoonhyeun Oum, C Chris Yun, Hyunsuk Shim
CXCR4 plays a crucial role in recruitment of inflammatory cells to inflammation sites at the beginning of the disease process. Modulating CXCR4 functions presents a new avenue for anti-inflammatory strategies. However, using CXCR4 antagonists for a long term usage presents potential serious side effect due to their stem cell mobilizing property. We have been developing partial CXCR4 antagonists without such property. A new computer-aided drug design program, the FRESH workflow, was used for anti-CXCR4 lead compound discovery and optimization, which coupled both compound library building and CXCR4 docking screens in one campaign...
November 24, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27914066/computational-tools-for-allosteric-drug-discovery-site-identification-and-focus-library-design
#8
Wenkang Huang, Ruth Nussinov, Jian Zhang
Allostery is an intrinsic phenomenon of biological macromolecules involving regulation and/or signal transduction induced by a ligand binding to an allosteric site distinct from a molecule's active site. Allosteric drugs are currently receiving increased attention in drug discovery because drugs that target allosteric sites can provide important advantages over the corresponding orthosteric drugs including specific subtype selectivity within receptor families. Consequently, targeting allosteric sites, instead of orthosteric sites, can reduce drug-related side effects and toxicity...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27913811/discovery-of-piperlongumine-as-a-potential-novel-lead-for-the-development-of-senolytic-agents
#9
Yingying Wang, Jianhui Chang, Xingui Liu, Xuan Zhang, Suping Zhang, Xin Zhang, Daohong Zhou, Guangrong Zheng
Accumulating evidence indicates that senescent cells play an important role in many age-associated diseases. The pharmacological depletion of senescent cells (SCs) with a "senolytic agent", a small molecule that selectively kills SCs, is a potential novel therapeutic approach for these diseases. Recently, we discovered ABT-263, a potent and highly selective senolytic agent, by screening a library of rationally-selected compounds. With this screening approach, we also identified a second senolytic agent called piperlongumine (PL)...
November 19, 2016: Aging
https://www.readbyqxmd.com/read/27913419/benzene-degradation-by-variovorax-sp-within-a-coal-tar-contaminated-groundwater-microbial-community
#10
Kevin M Posman, Christopher M DeRito, Eugene L Madsen
: Investigations of environmental microbial communities are crucial for the discovery of populations capable of degrading hazardous compounds and may lead to improved bioremediation strategies. The goal of this study was to identify microorganisms responsible for aerobic benzene degradation in coal-tar contaminated groundwater. Benzene degradation was monitored in laboratory incubations of well waters using gas chromatography mass spectrometry (GC/MS). Stable isotope probing (SIP) experiments using (13)C-benzene allowed us to obtain (13)C-labled community DNA; from this, 16S rRNA clone libraries identified γ- and β-Proteobacteria as the active benzene metabolizing microbial populations...
December 2, 2016: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/27910898/hydrogen-overproducing-nitrogenases-obtained-by-random-mutagenesis-and-high-throughput-screening
#11
Emma Barahona, Emilio Jiménez-Vicente, Luis M Rubio
When produced biologically, especially by photosynthetic organisms, hydrogen gas (H2) is arguably the cleanest fuel available. An important limitation to the discovery or synthesis of better H2-producing enzymes is the absence of methods for the high-throughput screening of H2 production in biological systems. Here, we re-engineered the natural H2 sensing system of Rhodobacter capsulatus to direct the emission of LacZ-dependent fluorescence in response to nitrogenase-produced H2. A lacZ gene was placed under the control of the hupA H2-inducible promoter in a strain lacking the uptake hydrogenase and the nifH nitrogenase gene...
December 2, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27909576/zika-antiviral-chemotherapy-identification-of-drugs-and-promising-starting-points-for-drug-discovery-from-an-fda-approved-library
#12
Bruno S Pascoalino, Gilles Courtemanche, Marli T Cordeiro, Laura H V G Gil, Lucio Freitas-Junior
Background The recent epidemics of Zika virus (ZIKV) implicated it as the cause of serious and potentially lethal congenital conditions such microcephaly and other central nervous system defects, as well as the development of the Guillain-Barré syndrome in otherwise healthy patients. Recent findings showed that anti-Dengue antibodies are capable of amplifying ZIKV infection by a mechanism similar to antibody-dependent enhancement, increasing the severity of the disease. This scenario becomes potentially catastrophic when the global burden of Dengue and the advent of the newly approved anti-Dengue vaccines in the near future are taken into account...
2016: F1000Research
https://www.readbyqxmd.com/read/27906188/large-scale-pharmacological-profiling-of-3d-tumor-models-of-cancer-cells
#13
Lesley A Mathews Griner, Xiaohu Zhang, Rajarshi Guha, Crystal McKnight, Ian S Goldlust, Madhu Lal-Nag, Kelli Wilson, Sam Michael, Steve Titus, Paul Shinn, Craig J Thomas, Marc Ferrer
The discovery of chemotherapeutic agents for the treatment of cancer commonly uses cell proliferation assays in which cells grow as two-dimensional (2D) monolayers. Compounds identified using 2D monolayer assays often fail to advance during clinical development, most likely because these assays do not reproduce the cellular complexity of tumors and their microenvironment in vivo. The use of three-dimensional (3D) cellular systems have been explored as enabling more predictive in vitro tumor models for drug discovery...
December 1, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27905914/development-of-a-gene-synthesis-platform-for-the-efficient-large-scale-production-of-small-genes-encoding-animal-toxins
#14
Ana Filipa Sequeira, Joana L A Brás, Catarina I P D Guerreiro, Renaud Vincentelli, Carlos M G A Fontes
BACKGROUND: Gene synthesis is becoming an important tool in many fields of recombinant DNA technology, including recombinant protein production. De novo gene synthesis is quickly replacing the classical cloning and mutagenesis procedures and allows generating nucleic acids for which no template is available. In addition, when coupled with efficient gene design algorithms that optimize codon usage, it leads to high levels of recombinant protein expression. RESULTS: Here, we describe the development of an optimized gene synthesis platform that was applied to the large scale production of small genes encoding venom peptides...
December 1, 2016: BMC Biotechnology
https://www.readbyqxmd.com/read/27903217/rational-drug-discovery-of-hcv-helicase-inhibitor-improved-docking-accuracy-with-multiple-seedings-of-autodock-vina-and-in-situ-minimization
#15
SeeKhai Lim, Rozana Othman, Rohana Yusof, ChoonHan Heh
BACKGROUND: Hepatitis C is a significant cause for end-stage liver diseases and liver transplantation which affects approximate 3% of the global populations. Despite the present of several direct antiviral agents in the treatment of hepatitis C, the standard treatment for HCV is accompanied by several drawbacks such as adverse side effects, high pricing of medications and the rapid emerging rate of resistant HCV variants. OBJECTIVES: To discover potential inhibitors for HCV helicase through an optimized in silico approach...
November 30, 2016: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/27901112/depletion-of-trna-halves-enables-effective-small-rna-sequencing-of-low-input-murine-serum-samples
#16
Alan Van Goethem, Nurten Yigit, Celine Everaert, Myrthala Moreno-Smith, Liselot M Mus, Eveline Barbieri, Frank Speleman, Pieter Mestdagh, Jason Shohet, Tom Van Maerken, Jo Vandesompele
The ongoing ascent of sequencing technologies has enabled researchers to gain unprecedented insights into the RNA content of biological samples. MiRNAs, a class of small non-coding RNAs, play a pivotal role in regulating gene expression. The discovery that miRNAs are stably present in circulation has spiked interest in their potential use as minimally-invasive biomarkers. However, sequencing of blood-derived samples (serum, plasma) is challenging due to the often low RNA concentration, poor RNA quality and the presence of highly abundant RNAs that dominate sequencing libraries...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27900857/stapled-peptides-by-late-stage-c-sp-3-h-activation
#17
Anaïs F M Noisier, Jesús García, Ioana A Ionuţ, Fernando Albericio
Despite the importance of stapled peptides for drug discovery, only few practical processes to prepare cross-linked peptides have been described; thus the structural diversity of available staple motifs is currently limited. At the same time, C-H activation has emerged as an efficient approach to functionalize complex molecules. Although there are many reports on the C-H functionalization of amino acids, examples of post-synthetic peptide C-H modification are rare and comprise almost only C(sp(2) )-H activation...
November 30, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27900785/a-tryptoline-ring-distortion-strategy-leads-to-complex-and-diverse-biologically-active-molecules-from-the-indole-alkaloid-yohimbine
#18
Nicholas Paciaroni, Ranjala Ratnayake, James Matthews, Verrill Norwood, Austin Arnold, Long Dang, Hendrik Luesch, Robert William Huigens Iii
High-throughput screening (HTS) is the primary driver to current drug discovery efforts. New therapeutic agents that enter the market are a direct reflection of the structurally simple compounds that make up screening libraries. Unlike medically relevant natural products (e.g., morphine), small molecules currently being screened have low fraction sp3 character and few, if any, stereogenic centers. Although simple compounds have been useful in drugging certain biological targets (e.g., protein kinases), more sophisticated targets (e...
November 29, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27900698/mining-microbial-signals-for-enhanced-biodiscovery-of-secondary-metabolites
#19
F Jerry Reen, Jose A Gutiérrez-Barranquero, Fergal O'Gara
The advent of metagenomics based biodiscovery has provided researchers with previously unforeseen access to the rich tapestry of natural bioactivity that exists in the biosphere. Unhindered by the "culturable bottleneck" that has severely limited the translation of the genetic potential that undoubtedly exists in nature, metagenomics nonetheless requires ongoing technological developments to maximize its efficacy and applicability to the discovery of new chemical entities.Here we describe methodologies for the detection and isolation of quorum sensing (QS) signal molecules from metagenomics libraries...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27900695/function-based-metagenomic-library-screening-and-heterologous-expression-strategy-for-genes-encoding-phosphatase-activity
#20
Genis A Castillo Villamizar, Heiko Nacke, Rolf Daniel
The release of phosphate from inorganic and organic phosphorus compounds can be mediated enzymatically. Phosphate-releasing enzymes, comprising acid and alkaline phosphatases, are recognized as useful biocatalysts in applications such as plant and animal nutrition, bioremediation and diagnostic analysis. Metagenomic approaches provide access to novel phosphatase-encoding genes. Here, we describe a function-based screening approach for rapid identification of genes conferring phosphatase activity from small-insert and large-insert metagenomic libraries derived from various environments...
2017: Methods in Molecular Biology
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