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https://www.readbyqxmd.com/read/28636311/insights-into-integrated-lead-generation-and-target-identification-in-malaria-and-tuberculosis-drug-discovery
#1
John Okombo, Kelly Chibale
New, safe and effective drugs are urgently needed to treat and control malaria and tuberculosis, which affect millions of people annually. However, financial return on investment in the poor settings where these diseases are mostly prevalent is very minimal to support market-driven drug discovery and development. Moreover, the imminent loss of therapeutic lifespan of existing therapies due to evolution and spread of drug resistance further compounds the urgency to identify novel effective drugs. However, the advent of new public-private partnerships focused on tropical diseases and the recent release of large data sets by pharmaceutical companies on antimalarial and antituberculosis compounds derived from phenotypic whole cell high throughput screening have spurred renewed interest and opened new frontiers in malaria and tuberculosis drug discovery...
June 21, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28635653/virtual-screening-against-phosphoglycerate-kinase-1-in-quest-of-novel-apoptosis-inhibitors
#2
Jie Xia, Bo Feng, Qianhang Shao, Yuhe Yuan, Xiang Simon Wang, Naihong Chen, Song Wu
Inhibition of apoptosis is a potential therapy to treat human diseases such as neurodegenerative disorders (e.g., Parkinson's disease), stroke, and sepsis. Due to the lack of druggable targets, it remains a major challenge to discover apoptosis inhibitors. The recent repositioning of a marketed drug (i.e., terazosin) as an anti-apoptotic agent uncovered a novel target (i.e., human phosphoglycerate kinase 1 (hPgk1)). In this study, we developed a virtual screening (VS) pipeline based on the X-ray structure of Pgk1/terazosin complex and applied it to a screening campaign for potential anti-apoptotic agents...
June 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28634758/a-general-double-library-selex-strategy-for-aptamer-selection-using-unmodified-nonimmobilized-targets
#3
Kyung Hyun Lee, Huaqiang Zeng
Aptamer discovery for unmodified nonimmobilized targets has been constantly presenting itself as a significant challenge to the research community. We demonstrate here a novel double library (DL) SELEX strategy and its usefulness and generality toward discovering both ssDNA- and RNA-based aptamers with nanomolar binding affinities toward unmodified targets of both small (e.g., doxycycline) and large (e.g., VEGF165) sizes. The same selection strategy further allows for concurrent selection of an aptamer pair, recognizing discrete epitopes on the same protein, from the same selection cycles for the sandwich aptamer pair-based biosensor development (e...
June 20, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28634080/nong-a-constituent-of-the-nonactin-biosynthetic-gene-cluster-regulates-nocardamine-synthesis-in-streptomyces-albus-j1074
#4
Wanki Park, Jung-Kyun Woo, Jongheon Shin, Ki-Bong Oh
Many factors regulate the expression of specialised secondary metabolite biosynthetic gene clusters, which have been recognised as important for the discovery of novel microbial natural products. A cosmid library based on genomic DNA of the marine-derived Streptomyces puniceus Act1085 was constructed and screened to identify a short gene cluster similar to the nonactin biosynthetic cluster. The ORFs of the gene cluster isolated had high amino acid sequence identity, from 82% to 96%, with corresponding ORFs of the nonactin biosynthetic gene cluster from S...
June 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28630801/characterization-of-the-transcriptome-and-est-ssr-development-in-boea-clarkeana-a-desiccation-tolerant-plant-endemic-to-china
#5
Ying Wang, Kun Liu, De Bi, Shoubiao Zhou, Jianwen Shao
BACKGROUND: Desiccation-tolerant (DT) plants can recover full metabolic competence upon rehydration after losing most of their cellular water (>95%) for extended periods of time. Functional genomic approaches such as transcriptome sequencing can help us understand how DT plants survive and respond to dehydration, which has great significance for plant biology and improving the drought tolerance of crops. Boea clarkeana Hemsl. (Gesneriaceae) is a DT dicotyledonous herb. Its genomic sequences characteristics remain unknown...
2017: PeerJ
https://www.readbyqxmd.com/read/28627758/spectral-library-based-glycopeptide-analysis-detection-of-circulating-galectin-3-binding-protein-in-pancreatic-cancer
#6
Eslam N Nigjeh, Ru Chen, Yasuko Allen-Tamura, Randall E Brand, Teresa A Brentnall, Sheng Pan
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by its late diagnosis, poor prognosis and rapid development of drug resistance. Using the data independent acquisition (DIA) technique, we applied a spectral library-based proteomic approach to analyze N-glycosylated peptides in human plasma, in the context of pancreatic cancer study. EXPERIMENTAL DESIGN: We extended the application of DIA to the quantification of N-glycosylated peptides enriched from plasma specimens from a clinically well-defined cohort that consists of patients with early stage PDAC, chronic pancreatitis and healthy subjects...
June 19, 2017: Proteomics. Clinical Applications
https://www.readbyqxmd.com/read/28622369/comparative-sequence-analysis-reveals-regulation-of-genes-in-developing-schistosomula-of-schistosoma-mansoni-exposed-to-host-portal-serum
#7
Wander de Jesus Jeremias, Flávio Marcos Gomes Araújo, Fábio Ribeiro Queiroz, Fabiano Sviatopolk Mirsky Pais, Ana Carolina Alves de Mattos, Anna Christina de Matos Salim, Paulo Marcos Zech Coelho, Guilherme Correa Oliveira, John Robert Kusel, Renata Guerra-Sá, Roney Santos Coimbra, Élio Hideo Babá
Once inside a vertebrate host after infection, individual schistosomula of the parasite Schistosoma mansoni find a new and complex environment, which requires quick adjustments for survival, such as those that allow it to avoid the innate immune response of the host. Thus, it is very important for the parasite to remain within the skin after entering the host for a period of about 3 days, at which time it can then reach the venous system, migrate to the lungs and, by the end of eighth day post-infection, it reach the portal venous system, while undergoing minimal changes in morphology...
2017: PloS One
https://www.readbyqxmd.com/read/28617230/predicting-anatomic-therapeutic-chemical-classification-codes-using-tiered-learning
#8
Thomas Olson, Rahul Singh
BACKGROUND: The low success rate and high cost of drug discovery requires the development of new paradigms to identify molecules of therapeutic value. The Anatomical Therapeutic Chemical (ATC) Code System is a World Health Organization (WHO) proposed classification that assigns multi-level codes to compounds based on their therapeutic, pharmacological and chemical characteristics as well as the in-vivo sites(s) of activity. The ability to predict ATC codes of compounds can assist in creation of high-quality chemical libraries for drug screening and in applications such as drug repositioning...
June 7, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28616931/database-for-rapid-dereplication-of-known-natural-products-using-data-from-ms-and-fast-nmr-experiments
#9
Carlos L Zani, Anthony R Carroll
The discovery of novel and/or new bioactive natural products from biota sources is often confounded by the reisolation of known natural products. Dereplication strategies that involve the analysis of NMR and MS spectroscopic data to infer structural features present in purified natural products in combination with database searches of these substructures provide an efficient method to rapidly identify known natural products. Unfortunately this strategy has been hampered by the lack of publically available and comprehensive natural product databases and open source cheminformatics tools...
June 15, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28615356/sulforaphane-reduces-hepatic-glucose-production-and-improves-glucose-control-in-patients-with-type-2-diabetes
#10
Annika S Axelsson, Emily Tubbs, Brig Mecham, Shaji Chacko, Hannah A Nenonen, Yunzhao Tang, Jed W Fahey, Jonathan M J Derry, Claes B Wollheim, Nils Wierup, Morey W Haymond, Stephen H Friend, Hindrik Mulder, Anders H Rosengren
A potentially useful approach for drug discovery is to connect gene expression profiles of disease-affected tissues ("disease signatures") to drug signatures, but it remains to be shown whether it can be used to identify clinically relevant treatment options. We analyzed coexpression networks and genetic data to identify a disease signature for type 2 diabetes in liver tissue. By interrogating a library of 3800 drug signatures, we identified sulforaphane as a compound that may reverse the disease signature...
June 14, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28613814/2-chloropropionamide-as-a-low-reactivity-electrophile-for-irreversible-small-molecule-probe-identification
#11
Dharmaraja Allimuthu, Drew J Adams
Resurgent interest in covalent target engagement in drug discovery has demonstrated that small molecules containing weakly reactive electrophiles can be safe and effective therapies. Several recently FDA-approved drugs feature an acrylamide functionality to selectively engage cysteine side chains of kinases (Ibrutinib, Afatinib, and Neratinib). Additional electrophilic functionalities whose reactivity is compatible with highly selective target engagement and in vivo application could open new avenues in covalent small molecule discovery...
June 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28613102/a-high-throughput-platform-for-population-reformatting-and-mammalian-expression-of-phage-display-libraries-to-enable-functional-screening-as-full-length-igg
#12
Xiaodong Xiao, Julie A Douthwaite, Yan Chen, Ben Kemp, Sara Kidd, Jennifer Percival-Alwyn, Alison Smith, Kate Goode, Bonnie Swerdlow, David Lowe, Herren Wu, William F Dall'Acqua, Partha S Chowdhury
Phage display antibody libraries are a rich resource for discovery of potential therapeutic antibodies. Single-chain variable fragment (scFv) libraries are the most common format due to the efficient display of scFv by phage particles and the ease by which soluble scFv antibodies can be expressed for high-throughput screening. Typically, a cascade of screening and triaging activities are performed, beginning with the assessment of large numbers of E. coli-expressed scFv, and progressing through additional assays with individual reformatting of the most promising scFv to full-length IgG...
June 14, 2017: MAbs
https://www.readbyqxmd.com/read/28600954/high-throughput-thermofluor-based-assays-for-inhibitor-screening-of-stat-sh2-domains
#13
Elvin D de Araujo, Pimyupa Manaswiyoungkul, Johan Israelian, Jisung Park, Karen Yuen, Shiva Farhangi, Angelika Berger-Becvar, Lubna Abu-Jazar, Patrick T Gunning
The development of STAT protein-specific inhibitors has been the focus of a number of drug discovery programs. STAT activation occurs through phosphorylation at the STAT SH2 domain, resulting in dimerization, translocation to the nucleus, and transcription of proliferative genes. Due to the functional significance of the SH2 domain in mediating multiple components of the STAT signalling cascade, many libraries of inhibitors have been designed to target the SH2 domain. This has triggered the requirement for effective high-throughput screening platforms for analyzing binding by larger chemical libraries to STAT proteins...
May 1, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28588643/molecular-cloning-expression-and-characterization-of-four-novel-thermo-alkaliphilic-enzymes-retrieved-from-a-metagenomic-library
#14
Mukil Maruthamuthu, Jan Dirk van Elsas
BACKGROUND: Enzyme discovery is a promising approach to aid in the deconstruction of recalcitrant plant biomass in an industrial process. Novel enzymes can be readily discovered by applying metagenomics on whole microbiomes. Our goal was to select, examine, and characterize eight novel glycoside hydrolases that were previously detected in metagenomic libraries, to serve biotechnological applications with high performance. RESULTS: Here, eight glycosyl hydrolase family candidate genes were selected from metagenomes of wheat straw-degrading microbial consortia using molecular cloning and subsequent gene expression studies in Escherichia coli...
2017: Biotechnology for Biofuels
https://www.readbyqxmd.com/read/28587923/generation-and-validation-of-intracellular-ubiquitin-variant-inhibitors-for-usp7-and-usp10
#15
Wei Zhang, Maria A Sartori, Taras Makhnevych, Kelly E Federowicz, Xiaohui Dong, Li Liu, Satra Nim, Aiping Dong, Jingsong Yang, Yanjun Li, Dania Haddad, Andreas Ernst, Dirk Heerding, Yufeng Tong, Jason Moffat, Sachdev S Sidhu
Post-translational modification of the p53 signaling pathway plays an important role in cell cycle progression and stress-induced apoptosis. Indeed, a large body of work has shown that dysregulation of p53 and its E3 ligase MDM2 by the ubiquitin-proteasome system (UPS) promotes carcinogenesis and malignant transformation. Thus, drug discovery efforts have focused on restoration of wild-type p53 activity or inactivation of oncogenic mutant p53 by targeted inhibition of UPS components, particularly key deubiquitinases (DUBs) of the ubiquitin-specific protease (USP) class...
June 3, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28584617/tumor-cells-growth-and-survival-time-with-the-ketogenic-diet-in-animal-models-a-systematic-review
#16
REVIEW
Soheila Khodadadi, Nafiseh Sobhani, Somaye Mirshekar, Reza Ghiasvand, Makan Pourmasoumi, Maryam Miraghajani, Somayeh Shahraki Dehsoukhteh
Recently, interest in targeted cancer therapies via metabolic pathways has been renewed with the discovery that many tumors become dependent on glucose uptake during anaerobic glycolysis. Also the inability of ketone bodies metabolization due to various deficiencies in mitochondrial enzymes is the major metabolic changes discovered in malignant cells. Therefore, administration of a ketogenic diet (KD) which is based on high in fat and low in carbohydrates might inhibit tumor growth and provide a rationale for therapeutic strategies...
2017: International Journal of Preventive Medicine
https://www.readbyqxmd.com/read/28584151/discovery-and-characterization-of-a-novel-cd4-binding-adnectin-with-potent-anti-hiv-activity
#17
David Wensel, Yongnian Sun, Zhufang Li, Sharon Zhang, Caryn Picarillo, Thomas McDonagh, David Fabrizio, Mark Cockett, Mark Krystal, Jonathan Davis
A novel fibronectin-based protein (Adnectin) HIV-1 inhibitor was generated using in vitro selection. This inhibitor binds to human CD4 with high affinity (3.9 nM) and inhibits viral entry at a step post-CD4 engagement and preceding membrane fusion. The progenitor sequence of this novel inhibitor was selected from a library of trillions of Adnectin variants using mRNA display, then further optimized for improved anti-viral and physical properties. The final optimized inhibitor exhibited full potency against a panel of 124 envelope (gp160) proteins spanning 11 subtypes, indicating broad spectrum activity...
June 5, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28583442/evolution-of-selective-sequencing-approaches-for-virus-discovery-and-virome-analysis
#18
REVIEW
Arvind Kumar, Satyapramod Murthy, Amit Kapoor
Recent advances in sequencing technologies have transformed the field of virus discovery and virome analysis. Once, mostly confined to the traditional Sanger sequencing based individual virus discovery, is now entirely replaced by high throughput sequencing (HTS) based virus metagenomics that can be used to characterize the nature and composition of entire viromes. To better harness the potential of HTS for study of viromes, sample preparation methodologies used different refinements to exclude amplification of non-viral components that can overshadow low-titer viruses...
June 2, 2017: Virus Research
https://www.readbyqxmd.com/read/28581894/identification-of-small-molecule-noncovalent-binders-utilizing-samdi-technology
#19
Erica C VanderPorten, Michael D Scholle, John Sherrill, John C Tran, Yichin Liu
In recent years, the ability to unambiguously identify complex mixtures of analytes with high accuracy and resolving power in a label-free format continues to expand the application of mass spectrometry (MS) in the drug discovery process. This advantage combined with improved instrumentation makes MS suitable for targets with limited alternative assays for high-throughput screening (HTS). We describe a novel screening format using Self-Assembled Monolayers and matrix-assisted laser Desorption Ionization (SAMDI) technology...
June 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28581721/a-fusion-protein-of-the-p53-transaction-domain-and-the-p53-binding-domain-of-the-oncoprotein-mdmx-as-an-efficient-system-for-high-throughput-screening-of-mdmx-inhibitors
#20
Rong Chen, Jingjing Zhou, Lingyun Qin, Yao Chen, Yongqi Huang, Huili Liu, Zhengding Su
In nearly half of cancers, the anticancer activity of p53 protein is often impaired by the overexpressed oncoprotein Mdm2 and its homologue, MdmX, demanding efficient therapeutics to disrupt the aberrant p53-MdmX/Mdm2 interactions to restore the p53 activity. While many potent Mdm2-specific inhibitors have already undergone clinical investigations, searching for MdmX-specific inhibitors has become very attractive, requiring a more efficient screening strategy for evaluating potential scaffolds or leads. In this work, considering that the intrinsic fluorescence residue Trp23 in the p53 transaction domain (p53p) plays an important role in determining the p53-MdmX/Mdm2 interactions, we constructed a fusion protein to utilize this intrinsic fluorescence signal to monitor high-throughput screening of a compound library...
June 14, 2017: Biochemistry
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