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https://www.readbyqxmd.com/read/28729722/structure-based-discovery-of-small-molecule-inhibitors-of-cariogenic-virulence
#1
Qiong Zhang, Bhavitavya Nijampatnam, Zhang Hua, Thao Nguyen, Jing Zou, Xia Cai, Suzanne M Michalek, Sadanandan E Velu, Hui Wu
Streptococcus mutans employs a key virulence factor, three glucosyltransferase (GtfBCD) enzymes to establish cariogenic biofilms. Therefore, the inhibition of GtfBCD would provide anti-virulence therapeutics. Here a small molecule library of 500,000 small molecule compounds was screened in silico against the available crystal structure of the GtfC catalytic domain. Based on the predicted binding affinities and drug-like properties, small molecules were selected and evaluated for their ability to reduce S. mutans biofilms, as well as inhibit the activity of Gtfs...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28726847/mapping-genome-wide-transcription-factor-binding-sites-using-dap-seq
#2
Anna Bartlett, Ronan C O'Malley, Shao-Shan Carol Huang, Mary Galli, Joseph R Nery, Andrea Gallavotti, Joseph R Ecker
To enable low-cost, high-throughput generation of cistrome and epicistrome maps for any organism, we developed DNA affinity purification sequencing (DAP-seq), a transcription factor (TF)-binding site (TFBS) discovery assay that couples affinity-purified TFs with next-generation sequencing of a genomic DNA library. The method is fast, inexpensive, and more easily scaled than chromatin immunoprecipitation sequencing (ChIP-seq). DNA libraries are constructed using native genomic DNA from any source of interest, preserving cell- and tissue-specific chemical modifications that are known to affect TF binding (such as DNA methylation) and providing increased specificity as compared with in silico predictions based on motifs from methods such as protein-binding microarrays (PBMs) and systematic evolution of ligands by exponential enrichment (SELEX)...
August 2017: Nature Protocols
https://www.readbyqxmd.com/read/28723234/flexible-small-molecular-anti-estrogens-with-n-n-dialkylated-2-5-diethoxy-4-morpholinoaniline-scaffold-targets-multiple-estrogen-receptor-conformations
#3
Bethany K Asare, Emmanuel Yawson, Rajendram V Rajnarayanan
Estrogen mediates various cellular processes including cell proliferation, differentiation, growth and mammary gland function. Estrogen Receptors (ERs) are expressed in 70% of breast cancers. Consequently, estrogen mediated ER signaling plays a critical role in breast cancer diagnosis, prognosis, and treatment. Estrogen Receptors are ligand-triggered transcription factors. However, in the absence of a cognate estrogenic ligand, ERs can be activated by a variety of other extracellular signals. Tamoxifen, an anti-estrogen that selectively targets ER, induces substantial regression of breast tumors and an increase in disease-free survival...
July 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28722147/surface-isoelectric-focusing-sief-with-carrier-ampholyte-ph-gradient
#4
Zhichao Wang, Cornelius Ivory, Adrienne R Minerick
Isoelectric focusing (IEF) is a powerful tool for amphoteric protein separations because of high sensitivity, bio-compatibility, and reduced complexity compared to chromatography or mechanical separation techniques. IEF miniaturization is attractive because it enables rapid analysis, easier adaptation to point of care applications, and smaller sample demands. However, existing small-scale IEF tools have not yet been able to analyze single protein spots from array libraries, which are ubiquitous in many pharmaceutical discovery and screening protocols...
July 19, 2017: Electrophoresis
https://www.readbyqxmd.com/read/28720326/piperidine-and-octahydropyrano-3-4-c-pyridine-scaffolds-for-drug-like-molecular-libraries-of-the-european-lead-factory
#5
Bharat D Narhe, Arjen C Breman, Jalindar Padwal, Dirk A L Vandenput, Joeri M Scheidt, Jorg C J Benningshof, Gijsbert A van der Marel, Herman S Overkleeft, Mario van der Stelt, Dmitri V Filippov
We report short and efficient scalable syntheses of enantiomerically pure (3R,4S)-3-(hydroxymethyl4-(hydroxyethyl))-piperidine and 1-hydroxymethyl-octahydro-1H-pyrano[3,4-c]pyridine scaffolds. The alkaloid core was readily synthesized from naturally occurring quinine and can serve as a valued starting point for drug-discovery. Cleavage of a terminal 1,2-diol and acid catalysed epoxide opening cyclization are the key steps involved. A number of members of a projected small-molecular library is synthesized for each scaffold...
July 10, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28718479/exploring-structural-complexity-in-the-discovery-and-self-assembly-of-a-family-of-nanoscale-chalcoxides-from-se8mo36-to-se26mo68
#6
Hong-Ying Zang, Jamie W Purcell, De-Liang Long, Haralampos N Miras, Leroy Cronin
Herein, we show the controlled generation of multi-component libraries based on the [MoS2O2](2+)/Mo(VI)O4(2-)/Se(IV)O3(2-)/C4O4(2-) system leading to the formation of a whole new family of nanosized molecular chalcoxides, {Se8Mo36} 1, {Se8Mo40} 2, {Se8Mo56} 3, {Se20Mo56} 4 and {Se26Mo68} 5, of the general formula {(MoO2S2)a(OH)b(Se(IV)O3)c(C4O4)d(MoO7)e}(n-), where a, b, c, d, e, n = [16, 20, 8, 6, 2, 20] for 1, [18, 24, 8, 6, 2, 20] for 2, [24, 32, 8, 8, 4, 24] for 3, [28, 32, 20, 8, 0, 32] for 4 and [34, 36, 26, 8, 0, 36] for 5...
July 18, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28717593/short-reads-from-honey-bee-apis-sp-sequencing-projects-reflect-microbial-associate-diversity
#7
Michael Gerth, Gregory D D Hurst
High throughput (or 'next generation') sequencing has transformed most areas of biological research and is now a standard method that underpins empirical study of organismal biology, and (through comparison of genomes), reveals patterns of evolution. For projects focused on animals, these sequencing methods do not discriminate between the primary target of sequencing (the animal genome) and 'contaminating' material, such as associated microbes. A common first step is to filter out these contaminants to allow better assembly of the animal genome or transcriptome...
2017: PeerJ
https://www.readbyqxmd.com/read/28717159/the-essential-genomic-landscape-of-the-commensal-bifidobacterium-breve-ucc2003
#8
Lorena Ruiz, Francesca Bottacini, Christine J Boinett, Amy K Cain, Mary O'Connell-Motherway, Trevor D Lawley, Douwe van Sinderen
Bifidobacteria are common gut commensals with purported health-promoting effects. This has encouraged scientific research into bifidobacteria, though recalcitrance to genetic manipulation and scarcity of molecular tools has hampered our knowledge on the precise molecular determinants of their health-promoting attributes and gut adaptation. To overcome this problem and facilitate functional genomic analyses in bifidobacteria, we created a large Tn5 transposon mutant library of the commensal Bifidobacterium breve UCC2003 that was further characterized by means of a Transposon Directed Insertion Sequencing (TraDIS) approach...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28715203/a-bioinorganic-approach-to-fragment-based-drug-discovery-targeting-metalloenzymes
#9
Seth M Cohen
Metal-dependent enzymes (i.e., metalloenzymes) make up a large fraction of all enzymes and are critically important in a wide range of biological processes, including DNA modification, protein homeostasis, antibiotic resistance, and many others. Consequently, metalloenzymes represent a vast and largely untapped space for drug development. The discovery of effective therapeutics that target metalloenzymes lies squarely at the interface of bioinorganic and medicinal chemistry and requires expertise, methods, and strategies from both fields to mount an effective campaign...
July 17, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28715199/jumping-hurdles-peptides-able-to-overcome-biological-barriers
#10
Macarena Sánchez-Navarro, Meritxell Teixidó, Ernest Giralt
The cell membrane, the gastrointestinal tract, and the blood-brain barrier (BBB) are good examples of biological barriers that define and protect cells and organs. They impose different levels of restriction, but they also share common features. For instance, they all display a high lipophilic character. For this reason, hydrophilic compounds, like peptides, proteins, or nucleic acids have long been considered as unable to bypass them. However, the discovery of cell-penetrating peptides (CPPs) opened a vast field of research...
July 17, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28714473/prioritizing-multiple-therapeutic-targets-in-parallel-using-automated-dna-encoded-library-screening
#11
Carl A Machutta, Christopher S Kollmann, Kenneth E Lind, Xiaopeng Bai, Pan F Chan, Jianzhong Huang, Lluis Ballell, Svetlana Belyanskaya, Gurdyal S Besra, David Barros-Aguirre, Robert H Bates, Paolo A Centrella, Sandy S Chang, Jing Chai, Anthony E Choudhry, Aaron Coffin, Christopher P Davie, Hongfeng Deng, Jianghe Deng, Yun Ding, Jason W Dodson, David T Fosbenner, Enoch N Gao, Taylor L Graham, Todd L Graybill, Karen Ingraham, Walter P Johnson, Bryan W King, Christopher R Kwiatkowski, Joël Lelièvre, Yue Li, Xiaorong Liu, Quinn Lu, Ruth Lehr, Alfonso Mendoza-Losana, John Martin, Lynn McCloskey, Patti McCormick, Heather P O'Keefe, Thomas O'Keeffe, Christina Pao, Christopher B Phelps, Hongwei Qi, Keith Rafferty, Genaro S Scavello, Matt S Steiginga, Flora S Sundersingh, Sharon M Sweitzer, Lawrence M Szewczuk, Amy Taylor, May Fern Toh, Juan Wang, Minghui Wang, Devan J Wilkins, Bing Xia, Gang Yao, Jean Zhang, Jingye Zhou, Christine P Donahue, Jeffrey A Messer, David Holmes, Christopher C Arico-Muendel, Andrew J Pope, Jeffrey W Gross, Ghotas Evindar
The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins...
July 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28712942/structure-based-discovery-of-clinically-approved-drugs-as-zika-virus-ns2b-ns3-protease-inhibitors-that-potently-inhibit-zika-virus-infection-in-vitro-and-in-vivo
#12
Shuofeng Yuan, Jasper Fuk-Woo Chan, Helena den-Haan, Kenn Ka-Heng Chik, Anna Jinxia Zhang, Chris Chung-Sing Chan, Vincent Kwok-Man Poon, Cyril Chik-Yan Yip, Winger Wing-Nga Mak, Zheng Zhu, Zijiao Zou, Kah-Meng Tee, Jian-Piao Cai, Kwok-Hung Chan, Jorge de la Peña, Horacio Pérez-Sánchez, José Pedro Cerón-Carrasco, Kwok-Yung Yuen
Zika virus (ZIKV) infection may be associated with severe complications in fetuses and adults, but treatment options are limited. We performed an in silico structure-based screening of a large chemical library to identify potential ZIKV NS2B-NS3 protease inhibitors. Clinically approved drugs belonging to different drug classes were selected among the 100 primary hit compounds with the highest predicted binding affinities to ZIKV NS2B-NS3-protease for validation studies. ZIKV NS2B-NS3 protease inhibitory activity was validated in most of the selected drugs and in vitro anti-ZIKV activity was identified in two of them (novobiocin and lopinavir-ritonavir)...
July 13, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28699534/discovery-and-development-of-atp-competitive-mtor-inhibitors-using-computational-approaches
#13
Yao Luo, Ling Wang
The mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism, and angiogenesis. This protein is an attractive target for new anticancer drug development. Significant progress has been made in hit discovery, lead optimization, drug candidate development and determination of the three-dimensional (3D) structure of mTOR. Computational methods have been applied to accelerate the discovery and development of mTOR inhibitors helping to model the structure of mTOR, screen compound databases, uncover structure-activity relationship (SAR) and optimize the hits, mine the privileged fragments and design focused libraries...
July 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28696944/mitoriboscins-mitochondrial-based-therapeutics-targeting-cancer-stem-cells-cscs-bacteria-and-pathogenic-yeast
#14
Bela Ozsvari, Marco Fiorillo, Gloria Bonuccelli, Anna Rita Cappello, Luca Frattaruolo, Federica Sotgia, Rachel Trowbridge, Richard Foster, Michael P Lisanti
The "endo-symbiotic theory of mitochondrial evolution" states that mitochondrial organelles evolved from engulfed aerobic bacteria, after millions of years of symbiosis and adaptation. Here, we have exploited this premise to design new antibiotics and novel anti-cancer therapies, using a convergent approach. First, virtual high-throughput screening (vHTS) and computational chemistry were used to identify novel compounds binding to the 3D structure of the mammalian mitochondrial ribosome. The resulting library of ~880 compounds was then subjected to phenotypic drug screening on human cancer cells, to identify which compounds functionally induce ATP-depletion, which is characteristic of mitochondrial inhibition...
July 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28695752/stabilization-of-protein-protein-interactions-in-drug-discovery
#15
Sebastian A Andrei, Eline Sijbesma, Michael Hann, Jeremy Davis, Gavin O'Mahony, Matthew W D Perry, Anna Karawajczyk, Jan Eickhoff, Luc Brunsveld, Richard G Doveston, Lech-Gustav Milroy, Christian Ottmann
PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis...
July 11, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28695517/high-throughput-colorimetric-assay-for-identifying-parp-1-inhibitors-using-a-large-small-molecule-collection
#16
Elena Kotova, Alexei V Tulin
Poly(ADP-ribose)polymerase 1 (PARP-1) protein became a popular target for treatment of several types of cancer. A number of PARP-1 inhibitors are currently in clinical trials. Most of them were designed competitors with NAD for a binding site on PARP-1 molecule. This strategy resulted in a discovery of mainly nucleotide-like PARP-1 inhibitors, which may target not only PARP-1 but also other pathways involving NAD and other nucleotides. Many cancer types demonstrate rapid development of resistance to NAD-like PARP-1 inhibitors...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28693421/lipidmatch-an-automated-workflow-for-rule-based-lipid-identification-using-untargeted-high-resolution-tandem-mass-spectrometry-data
#17
Jeremy P Koelmel, Nicholas M Kroeger, Candice Z Ulmer, John A Bowden, Rainey E Patterson, Jason A Cochran, Christopher W W Beecher, Timothy J Garrett, Richard A Yost
BACKGROUND: Lipids are ubiquitous and serve numerous biological functions; thus lipids have been shown to have great potential as candidates for elucidating biomarkers and pathway perturbations associated with disease. Methods expanding coverage of the lipidome increase the likelihood of biomarker discovery and could lead to more comprehensive understanding of disease etiology. RESULTS: We introduce LipidMatch, an R-based tool for lipid identification for liquid chromatography tandem mass spectrometry workflows...
July 10, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28689404/discovery-of-a-covalent-kinase-inhibitor-from-a-dna-encoded-small-molecule-library-%C3%A3-protein-library-selection
#18
Alix I Chan, Lynn M McGregor, Tara Jain, David R Liu
We previously reported interaction determination using unpurified proteins (IDUP), a method to selectively amplify DNA sequences encoding ligand:target pairs from a mixture of DNA-linked small molecules and unpurified protein targets in cell lysates. In this study, we applied IDUP to libraries of DNA-encoded bioactive compounds and DNA-tagged human kinases to identify ligand:protein binding partners out of 32 096 possible combinations in a single solution-phase library × library experiment. The results recapitulated known small molecule:protein interactions and also revealed that ethacrynic acid is a novel ligand and inhibitor of MAP2K6 kinase...
July 20, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28686847/development-and-implementation-of-an-hts-compatible-assay-for-the-discovery-of-selective-small-molecule-ligands-for-pre-micrornas
#19
Daniel A Lorenz, Steve Vander Roest, Martha J Larsen, Amanda L Garner
microRNAs (miRNAs) are small gene regulatory RNAs, and their expression has been found to be dysregulated in a number of human diseases. To facilitate the discovery of small molecules capable of selectively modulating the activity of a specific miRNA, we have utilized new high-throughput screening technology targeting Dicer-mediated pre-miRNA maturation. Pilot screening of ~50,000 small molecules and ~33,000 natural product extract libraries against pre-miR-21 processing indicated the potential of our assay for this goal, yielding a campaign Z' factor of 0...
July 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28682059/the-poisson-statistics-of-combinatorial-library-sampling-predict-false-discovery-rates-of-screening
#20
Andrew B MacConnell, Brian M Paegel
Microfluidic droplet-based screening of DNA-encoded one-bead-one-compound combinatorial libraries is a miniaturized, potentially widely distributable approach to small molecule discovery. In these screens, a microfluidic circuit distributes library beads into droplets of activity assay reagent, photochemically cleaves the compound from the bead, then incubates and sorts the droplets based on assay result for subsequent DNA sequencing-based hit compound structure elucidation. Pilot experimental studies revealed that Poisson statistics describe nearly all aspects of such screens, prompting the development of simulations to understand system behavior...
July 6, 2017: ACS Combinatorial Science
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