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Library Discovery

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https://www.readbyqxmd.com/read/28542505/alzhcpi-a-knowledge-base-for-predicting-chemical-protein-interactions-towards-alzheimer-s-disease
#1
Jiansong Fang, Ling Wang, Yecheng Li, Wenwen Lian, Xiaocong Pang, Hong Wang, Dongsheng Yuan, Qi Wang, Ai-Lin Liu, Guan-Hua Du
Alzheimer's disease (AD) is a complicated progressive neurodegeneration disorder. To confront AD, scientists are searching for multi-target-directed ligands (MTDLs) to delay disease progression. The in silico prediction of chemical-protein interactions (CPI) can accelerate target identification and drug discovery. Previously, we developed 100 binary classifiers to predict the CPI for 25 key targets against AD using the multi-target quantitative structure-activity relationship (mt-QSAR) method. In this investigation, we aimed to apply the mt-QSAR method to enlarge the model library to predict CPI towards AD...
2017: PloS One
https://www.readbyqxmd.com/read/28538738/solid-phase-synthesis-cyclization-and-site-specific-functionalization-of-aziridine-containing-tetrapeptides
#2
Benjamin K W Chung, Christopher J White, Andrei K Yudin
Cyclic tetrapeptides comprise a potent and selective class of molecules with a wide range of biological activities, including the phytotoxic activity of tentoxin and the histone deacetylase (HDAC) inhibitory effects of chlamydocin. The incorporation of a functional aziridine group within cyclic peptides enables their conformational control and allows for late-stage and site-selective functionalization of these molecules, thereby creating the potential for covalent protein labeling. This protocol describes the solid-phase synthesis, cyclization, and site-specific structural modification of aziridine-containing tetrapeptides...
June 2017: Nature Protocols
https://www.readbyqxmd.com/read/28537730/discovery-of-small-molecules-as-multi-toll-like-receptor-agonists-with-proinflammatory-and-anticancer-activities
#3
Lei Zhang, Varun Dewan, Hang Hubert Yin
Therapies based on activation of multiple Toll-like receptors (TLRs) may offer superior therapeutic profiles than that of single TLR activation. To discover new small molecules that could activate multiple TLRs, we performed a cell-based high-throughput screening of a small-molecule library based on TLR3-mediated NF-κB activation. Subsequent structural optimization and counter screening of other TLRs produced the first small molecule (CU-CPT24e) capable of simultaneously activating TLRs 3, 8, and 9. Biochemical studies demonstrated that CU-CPT24e could induce a strong immune response via the production of various cytokines in human monocytic THP-1 cells...
May 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28537594/switchable-regioselectivity-in-amine-catalysed-asymmetric-cycloadditions
#4
Zhi Zhou, Zhou-Xiang Wang, Yuan-Chun Zhou, Wei Xiao, Qin Ouyang, Wei Du, Ying-Chun Chen
Building small-molecule libraries with structural and stereogenic diversity plays an important role in drug discovery. The development of switchable intermolecular cycloaddition reactions from identical substrates in different regioselective fashions would provide an attractive protocol. However, this also represents a challenge in organic chemistry, because it is difficult to control regioselectivity to afford the products exclusively and at the same time achieve high levels of stereoselectivity. Here, we report the diversified cycloadditions of α'-alkylidene-2-cyclopentenones catalysed by cinchona-derived primary amines...
June 2017: Nature Chemistry
https://www.readbyqxmd.com/read/28537376/elucidation-of-the-molecular-determinants-for-optimal-pfos-adsorption-using-a-combinatorial-nanoparticle-library-approach
#5
Yin Liu, Gaoxing Su, Fei Wang, Jianbo Jia, Shuhuan Li, Linlin Zhao, Yali Shi, Yaqi Cai, Hao Zhu, Bin Zhao, Guibin Jiang, Hongyu Zhou, Bing Yan
Perfluorooctane sulfonate (PFOS) is persistently accumulated in the environment and in humans, causing various toxicities. To determine the key molecular determinants for optimal PFOS specificity and efficiency, we designed and synthesized a combinatorial gold nanoparticle (GNP) library consisting of 18 members with rationally diversified hydrophobic, electrostatic and fluorine-fluorine interaction components for PFOS bindings. According to our findings the electrostatic and F-F interactions between PFOS and nanoparticles are complementary...
May 24, 2017: Environmental Science & Technology
https://www.readbyqxmd.com/read/28531277/genome-wide-discovery-of-viral-micrornas-based-on-phylogenetic-analysis-and-structural-evolution-of-various-human-papillomavirus-subtypes
#6
Shun-Long Weng, Kai-Yao Huang, Julia Tzu-Ya Weng, Fang-Yu Hung, Tzu-Hao Chang, Tzong-Yi Lee
In mammals, microRNAs (miRNAs) play key roles in controlling posttranscriptional regulation through binding to the mRNAs of target genes. Recently, it was discovered that viral miRNAs may be involved in human cancers and diseases. It is likely that viral miRNAs help viruses enter the latent phase of their life cycle and become undetected by the host's immune system, while increasing the host's risk for cancer development. Cervical cancer is typically related to the infection of human papillomavirus (HPV) through sexual transmission...
May 20, 2017: Briefings in Bioinformatics
https://www.readbyqxmd.com/read/28531200/discovery-of-micrornas-during-early-spermatogenesis-in-chicken
#7
Lu Xu, Qixin Guo, Guobin Chang, Lingling Qiu, Xiangping Liu, Yulin Bi, Yu Zhang, Hongzhi Wang, Wei Lu, Lichen Ren, Ying Chen, Yang Zhang, Qi Xu, Guohong Chen
Spermatogenesis is a complex process that involves many elements. However, until now, little is known at the molecular level about spermatogenesis in poultry. Here we investigated microRNAs and their target genes that may be involved in germ cell development and spermatogonial in chicken. We used next-generation sequencing to analyze miRNA expression profiles in three types of germline cells: primordial germ cells (PGCs), spermatogonial stem cells (SSCs), and spermatogonia (Sp) during early stage of spermatogenesis...
2017: PloS One
https://www.readbyqxmd.com/read/28530833/discovery-of-small-molecules-for-repressing-cap-independent-translation-of-human-vascular-endothelial-growth-factor-hvegf-as-novel-anti-tumor-agents
#8
Shi-Ke Wang, Yue Wu, Xiao-Qin Wang, Guo-Tao Kuang, Qi Zhang, Shu-Ling Lin, Hui-Yun Liu, Jia-Heng Tan, Zhi-Shu Huang, Tian-Miao Ou
Angiogenesis is important in tumorigenesis and tumor progression. Human vascular endothelial growth factor (hVEGF) is an angiogenic growth factor that plays a crucial role in tumor progression. The G-rich region within the 5'-untranslated region (5'-UTR) of hVEGF mRNA can form a 'switchable' RNA G-quadruplex structure that is essential for a cap-independent translation initiation. We screened our small-molecule library for binders of this G-tract. One novel quinazoline derivative, compound 1, showed a significant specific interaction with the G-tract and destabilized the G-quadruplex structure...
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28529717/gene-length-and-detection-bias-in-single-cell-rna-sequencing-protocols
#9
Belinda Phipson, Luke Zappia, Alicia Oshlack
Background: Single cell RNA sequencing (scRNA-seq) has rapidly gained popularity for profiling transcriptomes of hundreds to thousands of single cells. This technology has led to the discovery of novel cell types and revealed insights into the development of complex tissues. However, many technical challenges need to be overcome during data generation. Due to minute amounts of starting material, samples undergo extensive amplification, increasing technical variability. A solution for mitigating amplification biases is to include unique molecular identifiers (UMIs), which tag individual molecules...
2017: F1000Research
https://www.readbyqxmd.com/read/28526787/development-of-multi-well-plate-methods-using-pure-cultures-of-methanogens-to-identify-new-inhibitors-for-suppressing-ruminant-methane-emissions
#10
M R Weimar, J Cheung, D Dey, C McSweeney, M Morrison, Y Kobayashi, W B Whitman, V Carbone, L R Schofield, R S Ronimus, G M Cook
Hydrogenotrophic methanogens typically require strictly anaerobic culturing conditions in glass tubes with overpressures of H2 and CO2 that are both time-consuming and costly. To increase the throughput for screening chemical compound libraries, 96-well microtiter plate methods for the growth of a marine (environmental) methanogen Methanococcus maripaludis strain S2 and the rumen methanogen Methanobrevibacter species AbM4 were developed. A number of key parameters (inoculum size, reducing agents for media preparation, duration of assay, inhibitor solvents and culture volume) were optimised to achieve robust and reproducible growth in a high-throughput microtiter plate format...
May 19, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28524077/highly-stereoselective-synthesis-of-a-compound-collection-based-on-the-bicyclic-scaffolds-of-natural-products
#11
Murali Annamalai, Stanimira Hristeva, Martyna Bielska, Raquel Ortega, Kamal Kumar
Despite the great contribution of natural products in the history of successful drug discovery, there are significant limitations that persuade the pharmaceutical industry to evade natural products in drug discovery research. The extreme scarcity as well as structural complexity of natural products renders their practical synthetic access and further modifications extremely challenging. Although other alternative technologies, particularly combinatorial chemistry, were embraced by the pharmaceutical industry to get quick access to a large number of small molecules with simple frameworks that often lack three-dimensional complexity, hardly any success was achieved in the discovery of lead molecules...
May 18, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28520400/femtomole-scale-high-throughput-screening-of-protein-ligands-with-droplet-based-thermal-shift-assay
#12
Wen-Wen Liu, Ying Zhu, Qun Fang
There is a great demand to measure protein-ligand interactions in rapid and low cost way. Here we developed a microfluidic droplet-based thermal shift assay (dTSA) system for high throughput screening of small-molecule protein ligands. The system is composed of a nanoliter droplet array chip, a microfluidic droplet robot, and a real-time fluorescence detection system. Total 324 assays could be performed in parallel in a single chip with an 18 × 18 droplet array. The consumption of dTSA for each protein or ligand sample was only 5 nL (femtomole scale), which is significantly reduced by over 3 orders of magnitude compared with those in 96 or 384-well plate-based systems...
May 18, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28516777/improvements-in-mass-spectrometry-assay-library-generation-for-targeted-proteomics
#13
Johan Teleman, Simon Hauri, Johan Malmström
In data independent acquisition mass spectrometry (DIA-MS), targeted extraction of peptide signals in silico using mass spectrometry assay libraries is a successful method for the identification and quantification of proteins. Still, it remains unclear if high quality assay libraries with more accurate peptide ion coordinates can improve peptide target identification rates in DIA analysis. In this study, we systematically improved and evaluated the common algorithmic steps for assay library generation and demonstrate that increased assay quality results in substantially higher identification rates of peptide targets from mouse organ protein lysates measured by DIA-MS...
May 18, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28513756/divergent-synthesis-of-biflavonoids-yields-novel-inhibitors-of-the-aggregation-of-amyloid-%C3%AE-1-42
#14
Tze Han Sum, Tze Jing Sum, Súil Collins, Warren R J D Galloway, David G Twigg, Florian Hollfelder, David R Spring
Biflavonoids are associated with a variety of biologically useful properties. However, synthetic biflavonoids are poorly explored within drug discovery. There is considerable structural diversity possible within this compound class and large regions of potentially biologically relevant biflavonoid chemical space remain untapped or underexplored. Herein, we report the development of a modular and divergent strategy towards biflavonoid derivatives which enabled the step-economical preparation of a structurally diverse collection of novel unnatural biflavonoids...
May 17, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28507705/acid-and-au-i-mediated-synthesis-of-hexathymidine-dna-heterocycle-chimeras-an-efficient-entry-to-dna-encoded-libraries-inspired-by-drug-structures
#15
Mateja Klika Škopić, Hazem Salamon, Olivia Bugain, Kathrin Jung, Anne Gohla, Lara J Doetsch, Denise Dos Santos, Avinash Bhat, Bernd Wagner, Andreas Brunschweiger
Libraries of DNA-tagged compounds are a validated screening technology for drug discovery. They are synthesized through combinatorial iterations of alternated coding and preparative synthesis steps. Thus, large chemical space can be accessed for target-based screening. However, the need to preserve the functionality of the DNA tag severely restricts the choice of chemical methods for library synthesis. Acidic organocatalysts, transition metals, and oxidants furnish diverse drug-like structures from simple starting materials, but cause loss of genetic information by depurination...
May 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28504676/developing-spindlin1-small-molecule-inhibitors-by-using-protein-microarrays
#16
Narkhyun Bae, Monica Viviano, Xiaonan Su, Jie Lv, Donghang Cheng, Cari Sagum, Sabrina Castellano, Xue Bai, Claire Johnson, Mahmoud Ibrahim Khalil, Jianjun Shen, Kaifu Chen, Haitao Li, Gianluca Sbardella, Mark T Bedford
The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the 'druggability' of epigenetic effector molecules. The small-molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains and, with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs, we screened a protein-domain microarray of human methyllysine effector molecules to rapidly detect compounds with new binding profiles with either increased or decreased specificity...
May 15, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28503119/targeting-hiv-1-envelope-proteins-using-a-fragment-discovery-all-atom-computational-algorithm
#17
Michael H Peters
INTRODUCTION: HIV viral envelope proteins are targets for small inhibitor molecules aimed at disrupting the cellular entry process. Potential peptide-class inhibitor molecules (rDNA drugs) have been previously identified, with mixed results, through biomimicry and phage display experimental methods. Here we describe a new approach based on computational fragment discovery. The method has the potential to not only optimize peptide binding affinity but also to rapidly produce alternative inhibitors against mutated strains...
April 2017: Current Enzyme Inhibition
https://www.readbyqxmd.com/read/28502178/diverted-total-synthesis-of-carolacton-inspired-analogs-yields-three-distinct-phenotypes-in-streptococcus-mutans-biofilms
#18
Amy E Solinski, Alexander B Koval, Richard S Brzozowski, Kelly R Morrison, Americo J Fraboni, Carrie E Carson, Anisa R Eshraghi, Guangfeng Zhou, Robert G Quivey, Vincent A Voelz, Bettina A Buttaro, William M Wuest
The oral microbiome is a dynamic environment inhabited by both commensals and pathogens. Among these is Streptococcus mutans, the causative agent of dental caries, the most prevalent childhood disease. Carolacton has remarkably specific activity against S. mutans, causing acid-mediated cell death during biofilm formation; however, its complex structure limits its utility. Herein, we report the diverted total synthesis and biological evaluation of a rationally designed library of simplified analogs that unveiled three unique biofilm phenotypes further validating the role of natural product synthesis in the discovery of new biological phenomena...
May 17, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28501997/using-laser-capture-microdissection-to-isolate-cortical-laminae-in-nonhuman-primate-brain
#19
Brian A Corgiat, Claudius Mueller
Laser capture microdissection (LCM) is a technique that allows procurement of an enriched cell population from a heterogeneous tissue sample under direct microscopic visualization. Fundamentally, laser capture microdissection consists of three main steps: (1) visualizing the desired cell population by microscopy, (2) melting a thermolabile polymer onto the desired cell populations using infrared laser energy to form a polymer-cell composite (capture method) or photovolatizing a region of tissue using ultraviolet laser energy (cutting method), and (3) removing the desired cell population from the heterogeneous tissue...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28501621/discovery-of-a-novel-prolyl-trna-synthetase-inhibitor-and-elucidation-of-its-binding-mode-to-the-atp-site-in-complex-with-l-proline
#20
Ryutaro Adachi, Kengo Okada, Robert Skene, Kazumasa Ogawa, Masanori Miwa, Kazuhiro Tsuchinaga, Shoichi Ohkubo, Tsutomu Henta, Tomohiro Kawamoto
Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase family of enzymes and catalyzes the synthesis of prolyl-tRNA(Pro) using ATP, l-proline, and tRNA(Pro) as substrates. An ATP-dependent PRS inhibitor, halofuginone, was shown to suppress autoimmune responses, suggesting that the inhibition of PRS is a potential therapeutic approach for inflammatory diseases. Although a few PRS inhibitors have been derivatized from natural sources or substrate mimetics, small-molecule human PRS inhibitors have not been reported...
May 10, 2017: Biochemical and Biophysical Research Communications
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