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Library Discovery

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https://www.readbyqxmd.com/read/28821136/discovery-of-enzymatically-depolymerized-heparins-capable-of-treating-bleomycin-induced-pulmonary-injury-and-fibrosis-in-mice
#1
Yishu Yan, Shanshan Du, Yang Ji, Nan Su, Yi Wang, Xiang Mei, Wenming Zhu, Dong He, Yuan Lu, Chong Zhang, Xin-Hui Xing
Heparin has recently been shown to slow down idiopathic pulmonary fibrosis (IPF) process and improve survival of patients in some cases. To improve the anti-IPF function while minimizing their side effects, we developed heparin libraries with different structures depolymerized by single or combined heparinases, and systematically screened the efficacy of the different heparins for treatment of Bleomycin-induced pulmonary injury and fibrosis using mice model. Then we characterized the structural properties of the components capable of treating pulmonary injury and fibrosis by use of chip-based amide hydrophilic interaction chromatography (HILIC)-fourier transform (FT)-ESI-MS, polyacrylamide gel electrophoresis (PAGE), and high performance liquid chromatography (HPLC)...
October 15, 2017: Carbohydrate Polymers
https://www.readbyqxmd.com/read/28820984/identification-of-m-tuberculosis-antigens-in-the-sera-of-tuberculosis-patients-using-biomimetic-affinity-chromatography-in-conjunction-with-esi-cid-ms-ms
#2
Guorong Ma, Jinting Pan, Jincheng Han, Lina Gao, Shulin Zhang, Rongxiu Li
The profiling of abnormally-expressed proteins in host cells using mass spectrometry (MS) analysis is a classical approach for screening disease-associated biomarkers in clinical diagnosis. However, few pathogen-specific antigens can currently be detected in serum using this proteomic approach, since these are very low-abundant proteins that are easily masked by host high-abundant proteins. Identification of pathogen-specific antigens in the sera of tuberculosis patients is crucial for the clinical diagnosis of this infectious disease, especially in immune-compromised patients...
July 31, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28817930/identification-of-a-new-zinc-binding-chemotype-by-fragment-screening
#3
Panagiotis K Chrysanthopoulos, Prashant Mujumdar, Lucy A Woods, Olan Dolezal, Bin Ren, Thomas S Peat, Sally-Ann Poulsen
The discovery of a new zinc binding chemotype from screening a non-biased fragment library is reported. Using the orthogonal fragment screening methods of native state mass spectrometry and surface plasmon resonance a 3-unsubstituted-2,4-oxazolidinedione fragment was found to have low micromolar binding affinity to the zinc metalloenzyme carbonic anhydrase II (CA II). This affinity approached that of fragment sized primary benzene sulfonamides, the classical zinc binding group found in most CA II inhibitors...
August 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28817927/identification-of-biosynthetic-gene-clusters-from-metagenomic-libraries-using-pptase-complementation-in-a-streptomyces-host
#4
J Kipchirchir Bitok, Christophe Lemetre, Melinda A Ternei, Sean F Brady
The majority of environmental bacteria are not readily cultured in the lab, leaving the natural products they make inaccessible using culture-dependent discovery methods. Cloning and heterologous expression of DNA extracted from environmental samples (environmental DNA, eDNA) provides a means of circumventing this discovery bottleneck. To facilitate the identification of clones containing biosynthetic gene clusters, we developed a model heterologous expression reporter strain Streptomyces albus::bpsA ΔPPTase...
September 1, 2017: FEMS Microbiology Letters
https://www.readbyqxmd.com/read/28817640/evaluation-of-multilocus-marker-efficacy-for-delineating-mangrove-species-of-west-coast-india
#5
Ankush Ashok Saddhe, Rahul Arvind Jamdade, Kundan Kumar
The plant DNA barcoding is a complex and requires more than one marker(s) as compared to animal barcoding. Mangroves are diverse estuarine ecosystem prevalent in the tropical and subtropical zone, but anthropogenic activity turned them into the vulnerable ecosystem. There is a need to build a molecular reference library of mangrove plant species based on molecular barcode marker along with morphological characteristics. In this study, we tested the core plant barcode (rbcL and matK) and four promising complementary barcodes (ITS2, psbK-psbI, rpoC1 and atpF-atpH) in 14 mangroves species belonging to 5 families from West Coast India...
2017: PloS One
https://www.readbyqxmd.com/read/28815923/biophysical-screening-of-a-focused-library-for-the-discovery-of-cyp121-inhibitors-as-novel-antimycobacterials
#6
Christian Brengel, Andreas Thomann, Alexander Schifrin, Giuseppe Allegretta, Ahmed A M Kamal, Joerg Haupenthal, Isabell Schnorr, Sang Hyun Cho, Scott Gary Franzblau, Martin Empting, Jens Eberhard, Rolf W Hartmann
The development of novel antimycobacterial agents against Mycobacterium tuberculosis (Mtb) is urgently required due to the appearance of multi-drug resistance (MDR) combined with a complicated long-term treatment. CYP121 was shown to be a promising novel target for inhibition of mycobacterial growth. In this study, we describe the rational discovery of new CYP121 inhibitors by a systematic screening based on biophysical and microbiological methods. Best hits originating from only one structural class gave first information about molecular motifs required for binding and activity...
August 16, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28815505/preparing-mate-paired-illumina-libraries-using-cre-recombinase
#7
Ze Peng, Nandita Nath, Zhiying Zhao, Jeff L Froula, Jan-Fang Cheng, Feng Chen
Large insert mate pair reads have been used in de novo assembly and discovery of structural variants. We developed a new approach, Cre-LoxP inverse PCR paired end (CLIP-PE), which exploits the advantages of (1) Cre-LoxP recombination system to efficiently circularize large DNA fragments, (2) inverse PCR to enrich for the desired products that contain both ends of the large DNA fragments, and (3) use of restriction enzymes to introduce a recognizable junction site between ligated fragment ends. We have successfully created CLIP-PE libraries of up to 22 kb jumping pairs and demonstrated their ability to improve genome assemblies...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28813501/durum-wheat-mirnas-in-response-to-nitrogen-starvation-at-the-grain-filling-stage
#8
Diana L Zuluaga, Domenico De Paola, Michela Janni, Pasquale Luca Curci, Gabriella Sonnante
Durum wheat highly depends on nitrogen for seed development and yield, and the obtainment of varieties with a better nitrogen use efficiency is crucial to reduce production costs and environmental pollution. In this study, sequencing of two small RNA libraries obtained from tissues of Ciccio and Svevo cultivars grown under nitrogen starvation conditions produced 84 novel, and 161 conserved miRNAs. Of these, 7 novel and 13 known miRNAs were newly identified in this work. Quantitative PCR analysis of selected miRNAs highlighted that the expression levels of some of them depends on the tissue and on the cultivar, Svevo being the most responsive to nitrogen starvation...
2017: PloS One
https://www.readbyqxmd.com/read/28813418/mechanism-of-intracellular-allosteric-%C3%AE-2ar-antagonist-revealed-by-x-ray-crystal-structure
#9
Xiangyu Liu, Seungkirl Ahn, Alem W Kahsai, Kai-Cheng Meng, Naomi R Latorraca, Biswaranjan Pani, A J Venkatakrishnan, Ali Masoudi, William I Weis, Ron O Dror, Xin Chen, Robert J Lefkowitz, Brian K Kobilka
G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28813151/the-medicinal-and-biological-chemistry-mbc-library-an-efficient-source-on-new-hits
#10
Víctor Sebastián Pérez, Carlos Roca, Mahendra Awale, Jean-Louis Reymond, Ana Martínez, Carmen Gil, Nuria E Campillo
Identification of new hits is one of the biggest challenges in drug discovery. Creating a library of well-characterized drug-like compounds is a key step in this process. Our group has developed an in-house chemical library called Medicinal and Biological Chemistry (MBC) library. This collection has been successfully used to start several medicinal chemistry programs and developed in an accumulation of more than thirty years of experience in drug design and discovery of new drugs for unmet diseases. It contains over 1,000 compounds, mainly heterocyclic scaffolds...
August 16, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28811609/rapid-and-accurate-in-silico-solubility-screening-of-a-monoclonal-antibody-library
#11
Pietro Sormanni, Leanne Amery, Sofia Ekizoglou, Michele Vendruscolo, Bojana Popovic
Antibodies represent essential tools in research and diagnostics and are rapidly growing in importance as therapeutics. Commonly used methods to obtain novel antibodies typically yield several candidates capable of engaging a given target. The development steps that follow, however, are usually performed with only one or few candidates since they can be resource demanding, thereby increasing the risk of failure of the overall antibody discovery program. In particular, insufficient solubility, which may lead to aggregation under typical storage conditions, often hinders the ability of a candidate antibody to be developed and manufactured...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28810737/identification-of-the-colicin-v-bacteriocin-gene-cluster-by-functional-screening-of-a-human-microbiome-metagenomic-library
#12
Louis Cohen, Sun Han, Yun-Han Huang, Sean F Brady
The forces that shape human microbial ecology are complex. It is likely, that human microbiota, similarly to other microbiomes, use antibiotics as one way to establish an ecological niche. In this study, we use functional metagenomics to identify human microbial gene clusters that encode for antibiotic functions. Screening of a metagenomic library prepared from a healthy patient stool sample led to the identification of a family of clones with inserts that are 99% identical to a region of a virulence plasmid found in avian pathogenic Escherichia coli...
August 15, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28810078/discovery-of-key-physicochemical-structural-and-spatial-properties-of-rna-targeted-bioactive-ligands
#13
Brittany S Morgan, Jordan E Forte, Rebecca N Culver, Yuqi Zhang, Amanda E Hargrove
While myriad non-coding RNAs are known to be essential in cellular processes and misregulated in diseases, the development of RNA-targeted small molecule probes has met with limited success. To elucidate guiding principles for selective small molecule:RNA recognition, we analyzed cheminformatic and shape-based descriptors for 104 RNA-targeted ligands with demonstrated biological activity (RNA-targeted BIoactive ligaNd Database, RBIND). We then compared R-BIND to both FDA-approved small molecule drugs and RNA ligands without reported bioactivity...
August 15, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28809975/discovery-of-synthetic-small-molecules-that-enhance-the-number-of-stomata-c-h-functionalization-chemistry-for-plant-biology
#14
Asraa Ziadi, Naoyuki Uchida, Hiroe Kato, Rina Hisamatsu, Ayato Sato, Shinya Hagihara, Kenichiro Itami, Keiko U Torii
The increasing climate changes and global warming are leading to colossal agricultural problems such as abatement of food production and quality. As stomatal development is considered to play a key role in crop plant productivity and water-use efficiency, studying stomatal development is useful for understanding the productivity of plant systems for both natural and agricultural systems. Herein, we report the first-in-class synthetic small molecules enhancing the number of stomata in Arabidopsis thaliana that have been discovered by screening of the chemical library and further optimized by the Pd-catalyzed C-H arylation reaction...
August 15, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28809565/dipicolinic-acid-derivatives-as-inhibitors-of-new-delhi-metallo-%C3%AE-lactamase-1
#15
Allie Y Chen, Pei W Thomas, Alesha C Stewart, Alexander Bergstrom, Zishuo Cheng, Callie Miller, Christopher R Bethel, Steven H Marshall, Cy V Credille, Christopher L Riley, Richard C Page, Robert A Bonomo, Michael W Crowder, David L Tierney, Walter Fast, Seth M Cohen
The efficacy of β-lactam antibiotics is threatened by the emergence and global spread of metallo-β-lactamase-(MBL) mediated resistance, specifically New Delhi-Metallo-β- lactamase-1 (NDM-1). Utilizing fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-lactamases, IMP-1 and VIM-2, was identified. Based on 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure-activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes...
August 15, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28809009/docking-and-virtual-screening-in-drug-discovery
#16
Maria Kontoyianni
Stages in a typical drug discovery organization include target selection, hit identification, lead optimization, preclinical and clinical studies. Hit identification and lead optimization are very much intertwined with computational modeling. Structure-based virtual screening (VS) has been a staple for more than a decade now in drug discovery with its underlying computational technique, docking, extensively studied. Depending on the objective, the parameters for VS may change, but the overall protocol is very straightforward...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28808272/a-combinatorial-approach-for-the-discovery-of-cytochrome-p450-2d6-inhibitors-from-nature
#17
Johannes Hochleitner, Muhammad Akram, Martina Ueberall, Rohan A Davis, Birgit Waltenberger, Hermann Stuppner, Sonja Sturm, Florian Ueberall, Johanna M Gostner, Daniela Schuster
The human cytochrome P450 2D6 (CYP2D6) enzyme is part of phase-I metabolism and metabolizes at least 20% of all clinically relevant drugs. Therefore, it is an important target for drug-drug interaction (DDI) studies. High-throughput screening (HTS) assays are commonly used tools to examine DDI, but show certain drawbacks with regard to their applicability to natural products. We propose an in silico - in vitro workflow for the reliable identification of natural products with CYP2D6 inhibitory potential. In order to identify candidates from natural product-based databases that share similar structural features with established inhibitors, a pharmacophore model was applied...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28805376/discovery-and-biosensing-applications-of-diverse-rna-cleaving-dnazymes
#18
Meng Liu, Dingran Chang, Yingfu Li
DNA-based enzymes, or DNAzymes, are not known to exist in Nature but can be isolated from random-sequence DNA pools using test tube selection techniques. Since the report of the first DNAzyme in 1994, many catalytic DNA molecules for catalyzing wide-ranging chemical transformations have been isolated and studied. Our laboratory has a keen interest in searching for diverse DNAzymes capable of cleaving RNA-containing substrates, determining their sequence requirements and structural properties, and examining their potential as biosensors...
August 14, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28804942/metagenomic-alkaline-protease-from-mangrove-sediment
#19
Tharcilla B A Pessoa, Rachel P Rezende, Eric de Lima Silva Marques, Carlos P Pirovani, Thalis F Dos Santos, Ana C Dos Santos Gonçalves, Carla C Romano, Natielle C Dotivo, Ana C O Freitas, Luiz C Salay, João C T Dias
Functional screening of metagenomic libraries is an important tool for the discovery of new molecules. The metabolic diversity of microorganisms enables survival in harsh environments and is related to the production of enzymes. In this study, we identified a protease-producing clone from a metagenomic library derived from mangrove sediment. The protease was purified by ammonium sulphate precipitation and gel filtration chromatography, with a yield of 77.27% and a specific activity of 8.57 U μg(-1) . It had a molecular weight of approximately 70 kDa...
August 14, 2017: Journal of Basic Microbiology
https://www.readbyqxmd.com/read/28802632/discovery-of-potent-and-selective-cdk8-inhibitors-through-fbdd-approach
#20
Xingchun Han, Min Jiang, Chengang Zhou, Zheng Zhou, Zhiheng Xu, Lisha Wang, Alexander V Mayweg, Rui Niu, Tai-Guang Jin, Song Yang
A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability.
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
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