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Sample records for 11c-labelled compound libraries

  1. General method for the (11)C-labeling of 2-arylpropionic acids and their esters: construction of a PET tracer library for a study of biological events involved in COXs expression.

    PubMed

    Takashima-Hirano, Misato; Shukuri, Miho; Takashima, Tadayuki; Goto, Miki; Wada, Yasuhiro; Watanabe, Yasuyoshi; Onoe, Hirotaka; Doi, Hisashi; Suzuki, Masaaki

    2010-04-12

    Cyclooxygenase (COX) is a critical enzyme in prostaglandin biosynthesis that modulates a wide range of biological functions, such as pain, fever, and so on. To perform in vivo COX imaging by positron emission tomography (PET), we developed a method to incorporate (11)C radionuclide into various 2-arylpropionic acids that have a common methylated structure, particularly among nonsteroidal anti-inflammatory drugs (NSAIDs). Thus, we developed a novel (11)C-radiolabeling methodology based on rapid C-[(11)C]methylation by the reaction of [(11)C]CH(3)I with enolate intermediates generated from the corresponding esters under basic conditions. One-pot hydrolysis of the above [(11)C]methylation products also allows the synthesis of desired (11)C-incorporated acids. We demonstrated the utility of this method in the syntheses of six PET tracers, [(11)C]Ibuprofen, [(11)C]Naproxen, [(11)C]Flurbiprofen, [(11)C]Fenoprofen, [(11)C]Ketoprofen, and [(11)C]Loxoprofen. Notably, we found that their methyl esters were particularly useful as proradiotracers for a study of neuroinflammation. The microPET studies of rats with lipopolysaccharide (LPS)-induced brain inflammation clearly showed that the radioactivity of PET tracers accumulated in the inflamed region. Among these PET tracers, the specificity of [(11)C]Ketoprofen methyl ester was demonstrated by a blocking study. Metabolite analysis in the rat brain revealed that the methyl esters were initially taken up in the brain and then underwent hydrolysis to form pharmacologically active forms of the corresponding acids. Thus, we succeeded in general (11)C-labeling of 2-arylpropionic acids and their methyl esters as PET tracers of NSAIDs to construct a potentially useful PET tracer library for in vivo imaging of inflammation involved in COXs expression.

  2. Dosimetry of D- and L-enantiomers of /sup 11/C-labeled tryptophan and valine

    SciTech Connect

    Washburn, L.C.; Byrd, B.L.; Sun, T.T.; Crook, J.E.; Hubner, K.F.; Coffey, J.L.; Watson, E.E.

    1985-01-01

    We have previously reported the radiation dosimetry of /sup 11/C-labeled DL-tryptophan and DL-valine, as well as clinical pancreatic imaging studies with these agents. Because of significant uptake in both normal pancreas and in pancreatic tumors (thought to be due to the presence of the D-enantiomer), differential diagnosis of pancreatic carcinoma was not feasible. High-performance liquid chromatographic (HPLC) methods were developed for rapid resolution of /sup 11/C-labeled DL-tryptophan and DL-valine. Radiation dose estimates to the various organs in man were calculated for the D- and L-enantiomers of /sup 11/C-labeled tryptophan and valine, based on tissue distribution data in rats. The dose estimates were sufficiently low that 20-mCi doses of each of the enantiomeric amino acids were approved by the FDA for intravenous administration to humans. 21 refs., 3 tabs.

  3. Development of a (11)C-labeled tetrazine for rapid tetrazine-trans-cyclooctene ligation.

    PubMed

    Herth, Matthias M; Andersen, Valdemar L; Lehel, Szabolcs; Madsen, Jacob; Knudsen, Gitte M; Kristensen, Jesper L

    2013-05-08

    Tetrazine-trans-cyclooctene ligations are remarkably fast and selective reactions even at low micro-molar concentrations. In bioorthogonal radiochemistry, tools that enable conjugation of radioactive probes to pre-targeted vectors are of great interest. Herein, we describe the successful development of the first (11)C-labelled tetrazine and its reaction with trans-cyclooctenol.

  4. XAFS Model Compound Library

    DOE Data Explorer

    Newville, Matthew

    The XAFS Model Compound Library contains XAFS data on model compounds. The term "model" compounds refers to compounds of homogeneous and well-known crystallographic or molecular structure. Each data file in this library has an associated atoms.inp file that can be converted to a feff.inp file using the program ATOMS. (See the related Searchable Atoms.inp Archive at http://cars9.uchicago.edu/~newville/adb/) This Library exists because XAFS data on model compounds is useful for several reasons, including comparing to unknown data for "fingerprinting" and testing calculations and analysis methods. The collection here is currently limited, but is growing. The focus to date has been on inorganic compounds and minerals of interest to the geochemical community. [Copied, with editing, from http://cars9.uchicago.edu/~newville/ModelLib/

  5. Development of a modular system for the synthesis of PET [(11)C]labelled radiopharmaceuticals.

    PubMed

    Boschi, Stefano; Lodi, Filippo; Cicoria, Gianfranco; Raul Ledesma, Jorge; Knopp, Roger; Rizzello, Anna; Di Pierro, Donato; Trespidi, Silvia; Marengo, Mario

    2009-10-01

    [((11))C]labelled radiopharmaceuticals as N-[(11)C]methyl-choline ([(11)C]choline), l-(S-methyl-[(11)C])methionine ([(11)C]methionine) and [(11)C]acetate have gained increasing importance in clinical PET and for the routine production of these radiopharmaceuticals, simple and reliable modules are needed to produce clinically relevant radioactivity. On the other hand, flexible devices are needed not only for the routine synthesis but also for more complex applications as the development of new tracers. The aim of this work was the adaptation of an Eckert Ziegler modular system for easy routine synthesis of [(11)C]choline, [(11)C]methionine and [(11)C]acetate using components that account for straightforward scaling up and upgrades.

  6. (11)C-labeling and preliminary evaluation of vortioxetine as a PET radioligand.

    PubMed

    Andersen, Valdemar L; Hansen, Hanne D; Herth, Matthias M; Knudsen, Gitte M; Kristensen, Jesper L

    2014-06-01

    Vortioxetine is a new multi-modal drug against major depressive disorder with high affinity for a range of different serotonergic targets in the CNS. We report the (11)C-labeling of vortioxetine with [(11)C]MeI using a Suzuki-protocol that allows for the presence of an unprotected amine. Preliminary evaluation of [(11)C]vortioxetine in a Danish Landrace pig showed rapid brain uptake and brain distribution in accordance with the pharmacological profile, all though an unexpected high binding in cerebellum was also observed. [(11)C]vortioxetine displayed slow tracer kinetics with peak uptake after 60 min and with limited wash-out from the brain. Further studies are needed but this radioligand may prove to be a valuable tool in unraveling the clinical effects of vortioxetine. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Kinetics of 11C-labeled opiates in the brain of rhesus monkeys

    SciTech Connect

    Hartvig, P.; Bergstroem, K.; Lindberg, B.; Lundberg, P.O.; Lundqvist, H.; Langstroem, B.; Svaerd, H.; Rane, A.

    1984-07-01

    The regional uptake in the brain of Rhesus monkeys of i.v. administered 11C-labeled morphine, codeine, heroin and pethidine was studied by means of positron emission tomography. The technique measures the sum of parent drug and radiolabeled metabolites. (For the sake of simplicity the drug derived radioactivity is denoted by the drug name.) Morphine had a limited uptake to discrete areas of the brain. The maximum normalized uptake, with respect to dose per kilogram body weight, was about 0.2, i.e., 20% of the calculated activity if the drug had been evenly distributed throughout the body of the monkey. Maximum radioactivity appeared 30 to 45 min after injection. Morphine left the brain slowly with an estimated half-life of more than 2 hr. An area with a normalized uptake of about 1.0 was detected centrally in the lowest horizontal transsection of the skull. The origin of this area was identified as the pituitary. Codeine, heroin and pethidine were taken up to the brain to a larger extent than morphine, with maximum normalized uptakes of 2.6, 4.6 and 6.3, respectively. Maximum radioactivities of these drugs were achieved earlier and the elimination rates were faster than for morphine. Differences in the uptake of these drugs to the brain, as well as differences in time to maximal normalized uptake and rate of disappearance are considered to reflect differences in the lipophilic character between the drugs. Pethidine had the most rapid and extensive uptake followed by heroin, codeine and morphine in order of decreasing lipophilicity.

  8. Design of compound libraries for fragment screening

    NASA Astrophysics Data System (ADS)

    Blomberg, Niklas; Cosgrove, David A.; Kenny, Peter W.; Kolmodin, Karin

    2009-08-01

    Approaches to the design of libraries for fragment screening are illustrated with reference to a 20 k generic fragment screening library and a 1.2 k generic NMR screening library. Tools and methods for library design that have been developed within AstraZeneca are described, including Foyfi fingerprints and the Flush program for neighborhood characterization. It will be shown how Flush and the BigPicker, which selects maximally diverse sets of compounds, are used to apply the Core and Layer method for library design. Approaches to partitioning libraries into cocktails are also described.

  9. Validation of quantitation of regional myocardial blood flow in vivo with /sup 11/C-labeled human albumin microspheres and positron emission tomography. [Dogs

    SciTech Connect

    Wilson, R.A.; Shea, M.J.; De Landsheere, C.M.; Turton, D.; Brady, F.; Deanfield, J.E.; Selwyn, A.P.

    1984-10-01

    Use of radiolabeled microspheres is a standard method to measure regional myocardial perfusion in animals. Human albumin microspheres have been given safely to patients, but positron-emitting /sup 67/Ga-labeled human albumin microspheres are characterized by an unstable radiolabel. A new labeling procedure that covalently binds /sup 11/C to human albumin microspheres via /sup 11/CH/sub 3/I was developed. Seven open-chest and two closed-chest dogs were studied. Reference and /sup 11/C-labeled human albumin microspheres (2 to 25 mCi) were both injected into the left atrium. Positron tomographic images were obtained of the myocardial distribution of the /sup 11/C-labeled microspheres. Timed arterial withdrawal was used for both reference gamma-labeled microspheres and /sup 11/C-labeled human albumin microspheres. Regional myocardial perfusion calculated by this technique correlated well with values obtained with reference microspheres over a range of 0.2 to 3.5 ml/min/g. Thus, /sup 11/C human albumin microspheres are stable radiochemically and can be used as a quantitative measure of regional myocardial perfusion.

  10. Virtual screening of compound libraries.

    PubMed

    Cerqueira, Nuno M F S A; Sousa, Sérgio F; Fernandes, Pedro A; Ramos, Maria João

    2009-01-01

    During the last decade, Virtual Screening (VS) has definitively established itself as an important part of the drug discovery and development process. VS involves the selection of likely drug candidates from large libraries of chemical structures by using computational methodologies, but the generic definition of VS encompasses many different methodologies. This chapter provides an introduction to the field by reviewing a variety of important aspects, including the different types of virtual screening methods, and the several steps required for a successful virtual screening campaign within a state-of-the-art approach, from target selection to postfilter application. This analysis is further complemented with a small collection important VS success stories.

  11. HER2-positive tumors imaged within 1 hour using a site-specifically 11C-labeled Sel-tagged affibody molecule.

    PubMed

    Wållberg, Helena; Grafström, Jonas; Cheng, Qing; Lu, Li; Martinsson Ahlzén, Hanna-Stina; Samén, Erik; Thorell, Jan-Olov; Johansson, Katarina; Dunås, Finn; Olofsson, Maria Hägg; Stone-Elander, Sharon; Arnér, Elias S J; Ståhl, Stefan

    2012-09-01

    A rapid, reliable method for distinguishing tumors or metastases that overexpress human epidermal growth factor receptor 2 (HER2) from those that do not is highly desired for individualizing therapy and predicting prognoses. In vivo imaging methods are available but not yet in clinical practice; new methodologies improving speed, sensitivity, and specificity are required. A HER2-binding Affibody molecule, Z(HER2:342), was recombinantly fused with a C-terminal selenocysteine-containing tetrapeptide Sel-tag, allowing site-specific labeling with either (11)C or (68)Ga, followed by biodistribution studies with small-animal PET. Dosimetry data for the 2 radiotracers were compared. Imaging of HER2-expressing human tumor xenografts was performed using the (11)C-labeled Affibody molecule. Both the (11)C- and (68)Ga-labeled tracers initially cleared rapidly from the blood, followed by a slower decrease to 4-5 percentage injected dose per gram of tissue at 1 h. Final retention in the kidneys was much lower (>5-fold) for the (11)C-labeled protein, and its overall absorbed dose was considerably lower. (11)C-Z(HER2:342) showed excellent tumor-targeting capability, with almost 10 percentage injected dose per gram of tissue in HER2-expressing tumors within 1 h. Specificity was demonstrated by preblocking binding sites with excess ligand, yielding significantly reduced radiotracer uptake (P = 0.002), comparable to uptake in tumors with low HER2 expression. To our knowledge, the Sel-tagging technique is the first that enables site-specific (11)C-radiolabeling of proteins. Here we present the finding that, in a favorable combination between radionuclide half-life and in vivo pharmacokinetics of the Affibody molecules, (11)C-labeled Sel-tagged Z(HER2:342) can successfully be used for rapid and repeated PET studies of HER2 expression in tumors.

  12. Synthesis and in vitro cellular uptake of 11C-labeled 5-aminolevulinic acid derivative to estimate the induced cellular accumulation of protoporphyrin IX.

    PubMed

    Suzuki, Chie; Kato, Koichi; Tsuji, Atsushi B; Kikuchi, Tatsuya; Zhang, Ming-Rong; Arano, Yasushi; Saga, Tsuneo

    2013-08-15

    Protoporphyrin IX (PpIX) accumulation induced by exogenous 5-aminolevulinic acid (ALA) in tumors affects the therapeutic efficacy of ALA-based photodynamic and sonodynamic therapies. To develop a new imaging probe to estimate the ALA-induced PpIX accumulation, (11)C-labeled ALA analog (4), an ALA-dehydratase inhibitor, was radiosynthesized via (11)C-methylation of a Schiff-base-activated precursor in the presence of tetrabutylammonium fluoride, followed by the hydrolysis of ester and imine groups. The cellular uptake of 4 linearly increased with time and was inhibited by ALA and other transporter competitors. Monitoring analog 4 with positron emission tomography might be useful to estimate the ALA-induced PpIX accumulation in tumors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Design, Synthesis, and Evaluation of a Low-Molecular-Weight (11)C-Labeled Tetrazine for Pretargeted PET Imaging Applying Bioorthogonal in Vivo Click Chemistry.

    PubMed

    Denk, Christoph; Svatunek, Dennis; Mairinger, Severin; Stanek, Johann; Filip, Thomas; Matscheko, Dominik; Kuntner, Claudia; Wanek, Thomas; Mikula, Hannes

    2016-07-20

    A low-molecular-weight tetrazine labeled with the short-lived positron emitter carbon-11 was developed as a bioorthogonal PET probe for pretargeted imaging. A method for efficient and fast synthesis of this imaging agent is presented using radiolabeling of a readily available precursor. High reactivity with trans-cyclooctenes was observed and in vivo investigations including PET/MR scanning showed homogeneous biodistribution, good metabolic stability, and rapid excretion in naive mice. These properties are key to the success of bioorthogonal (11)C-PET imaging, which has been shown in a simple pretargeting experiment using TCO-modified mesoporous silica nanoparticles. Overall, this (11)C-labeled tetrazine represents a highly versatile and advantageous chemical tool for bioorthogonal PET imaging and enables pretargeting approaches using carbon-11 for the first time.

  14. Quantitative ex vivo and in vitro receptor autoradiography using 11C-labeled ligands and an imaging plate: a study with a dopamine D2-like receptor ligand [11C]nemonapride.

    PubMed

    Ishiwata, K; Ogi, N; Tanaka, A; Senda, M

    1999-04-01

    Ex vivo and in vitro autoradiography (ARG) with radioluminography is a useful technique to characterize newly developed 11C-labeled positron emission tomography (PET) tracers and to apply them to biological and pharmacological studies. In this report, we have described a method of evaluating the radioactivity distribution quantitatively in ex vivo and in vitro ARG using imaging plates and a dopamine D2-like receptor ligand [11C]nemonapride as a model compound. The photo-stimulated luminescence (PSL) values of the rat brain section provided by the imaging plates showed an excellent linear relationship with the radioactivity in a wide range under constant slice-thickness, although the PSL values slightly decreased with increasing slice-thickness both in ex vivo and in vitro ARG. The injection dose of 11C-tracers for ex vivo ARG was also discussed. We found saturable binding sites of [11C]nemonapride in the cortex besides the striatum both ex vivo and in vitro.

  15. Development of Chemical Compound Libraries for In Silico Drug Screening.

    PubMed

    Fukunishi, Yoshifumi; Lintuluoto, Masami

    2010-01-01

    Chemical compound libraries are the basic database for virtual (in silico) drug screening, and the number of entries has reached 20 million. Many drug-like compound libraries for virtual drug screening have been developed and released. In this review, the process of constructing a database for virtual screening is reviewed, and several popular databases are introduced. Several kinds of focused libraries have been developed. The author has developed databases for metalloproteases, and the details of the libraries are described. The library for metalloproteases was developed by improving the generation of the dominant-ion forms. For instance, the SH group is treated as S- in this library while all SH groups are protonated in the conventional libraries. In addition, metal complexes were examined as new candidates of drug-like compounds. Finally, a method for generating chemical space is introduced, and the diversity of compound libraries is discussed.

  16. Receptor binding and selectivity of three 11C-labelled dopamine receptor antagonists in the brain of rhesus monkeys studied with positron emission tomography.

    PubMed

    Hartvig, P; Eckernäs, S A; Ekblom, B; Lindström, L; Lundqvist, H; Axelsson, S; Fasth, K J; Gullberg, P; Långström, B

    1988-04-01

    The regional distribution of 3 11C-labelled dopamine receptor antagonists, N-methyl spiperone, raclopride and clozapine, in the brain of Rhesus monkeys was studied by positron emission tomography (PET). The measured radioactivities in the striatal area were similar for the 3 antagonists, although the highest selectivity as compared to cerebellum was found for 11C-raclopride 60 min after administration. The selectivity of the radiotracers for the serotonin and D2-dopamine receptors was evaluated after pretreatment of the monkeys with serotonin and dopamine receptor antagonists. 11C-N-methylspiperone and 11C-clozapine both bound to serotonin receptors in the frontal cortex and to D2-dopamine receptors in the striatal area. Raclopride was selectively bound to the D2-dopamine receptors. The radioactivities measured in the striatal area with cerebellum as reference were fitted to a 3-compartment model which made possible evaluation of receptor binding characteristics. The rate proportional to the association rate constant for the receptor, kon and number of receptors, Bmax, varied from 0.02-0.07 min-1 between the studied radiolabelled drugs, whereas the apparent dissociation rate was highest for clozapine. This means that clozapine had the lowest affinity for the receptors in the striatum, assuming that the Bmax values are identical. The observed difference in selective receptor binding and binding characteristics of the 3 tracers may have an influence both on the clinical efficacy and side effects of the studied dopamine receptor antagonists.

  17. Synthesis and evaluation in monkey of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo.

    PubMed

    Briard, Emmanuelle; Zoghbi, Sami S; Imaizumi, Masao; Gourley, Jonathan P; Shetty, H Umesha; Hong, Jinsoo; Cropley, Vanessa; Fujita, Masahiro; Innis, Robert B; Pike, Victor W

    2008-01-10

    We sought to develop (11)C-labeled ligands for sensitive imaging of brain peripheral benzodiazepine receptors (PBR) in vivo. Two aryloxyanilides with high affinity for PBR were identified and synthesized, namely, N-acetyl- N-(2-methoxycarbonylbenzyl)-2-phenoxyaniline ( 3, PBR01) and N-(2-methoxybenzyl)- N-(4-phenoxypyridin-3-yl)acetamide ( 10, PBR28). 3 was hydrolyzed to 4, which was esterified with [ (11)C]iodomethane to provide [ (11)C] 3. The O-desmethyl analogue of 10 was converted into [ (11)C] 10 with [ (11)C]iodomethane. [ (11)C] 3 and [ (11)C] 10 were each injected into monkey to assess their brain kinetics with positron emission tomography (PET). After administration of either radioligand there was moderately high brain uptake of radioactivity. Receptor blocking and displacement experiments showed that a high proportion of this radioactivity was bound specifically to PBR. In monkey and rat, 3 and 10 were rapidly metabolized by ester hydrolysis and N-debenzylation, respectively, each to a single polar radiometabolite. [ (11)C] 3 and [ (11)C] 10 are effective for imaging PBR in monkey brain. [ (11)C] 10 especially warrants further evaluation in human subjects.

  18. [18F]- and [11C]-Labeled N-benzyl-isatin sulfonamide analogues as PET tracers for apoptosis: synthesis, radiolabeling mechanism, and in vivo imaging of apoptosis in Fas-treated mice

    PubMed Central

    Zhou, Dong; Chu, Wenhua; Chen, Delphine L.; Wang, Qi; Reichert, David E.; Rothfuss, Justin; D'Avignon, Andre; Welch, Michael J.; Mach, Robert H.

    2011-01-01

    Summary The radiolabeled isatin sulfonamide caspase-3 inhibitor, [18F]2 (WC-II-89), is a potential PET radiotracer for noninvasive imaging of apoptosis. The radiolabeling mechanism was studied by 13C NMR, ESI/MS, and computational calculations. It was found that the high electrophilicity of the C3 carbonyl group in the isatin ring, which served as a trap for [18F]fluoride, was responsible for the failure of the radiolabeling via nucleophilic substitution of the mesylate group in 7a by [18F]fluoride. Once treated with a strong base, 7a opened the isatin ring completely to form an isatinate intermediate 16, which lost the ability to trap [18F]fluoride, thereby allowing the displacement of the mesylate group to afford the 18F-labeled isatinate 17. [18F]17 can be converted to isatin [18F]2 efficiently under acidic conditions. The ring-opening and re-closure of the isatin ring under basic and acidic conditions were confirmed by reversed phase HPLC analysis, ESI/MS and 13C NMR studies. Computational studies of model compounds also support the above proposed mechanism. Similarly, the ring-opening and re-closure method was used successfully in the synthesis of the 11C labeled isatin sulfonamide analogue [11C]4 (WC-98). A microPET imaging study using [11C]4 in the Fas liver apoptosis model demonstrated retained activity in the target organ (liver) of the treated mice. Increased caspase-3 activation in the liver was verified by the fluorometric caspase-3 enzyme assay. Therefore, this study provides a useful method for radio-synthesis of isatin derivative radiotracers for PET and SPECT studies, and [11C]4 is a potential PET radiotracer for noninvasive imaging of apoptosis. PMID:19300818

  19. Compound Libraries: Recent Advances and Their Applications in Drug Discovery.

    PubMed

    Gong, Zhen; Hu, Guoping; Li, Qiang; Liu, Zhiguo; Wang, Fei; Zhang, Xuejin; Xiong, Jian; Li, Peng; Xu, Yan; Ma, Rujian; Chen, Shuhui; Li, Jian

    2017-04-25

    Hit identification is the starting point of small-molecule drug discovery and is therefore very important to the pharmaceutical industry. One of the most important approaches to identify a new hit is to screen a compound library using an in vitro assay. High-throughput screening has made great contributions to drug discovery since the 1990s but requires expensive equipment and facilities, and its success depends on the size of the compound library. Recent progress in the development of compound libraries has provided more efficient ways to identify new hits for novel drug targets, thereby helping to promote the development of the pharmaceutical industry, especially for first-in-class drugs. In this review, the sources and classification of compound libraries are summarized. The progress made in combinatorial libraries and DNA-encoded libraries is reviewed. Library design methods, especially for focused libraries, are introduced in detail. In the final part, the status of the compound libraries at WuXi is reported. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Automatic analysis of quantitative NMR data of pharmaceutical compound libraries.

    PubMed

    Liu, Xuejun; Kolpak, Michael X; Wu, Jiejun; Leo, Gregory C

    2012-08-07

    In drug discovery, chemical library compounds are usually dissolved in DMSO at a certain concentration and then distributed to biologists for target screening. Quantitative (1)H NMR (qNMR) is the preferred method for the determination of the actual concentrations of compounds because the relative single proton peak areas of two chemical species represent the relative molar concentrations of the two compounds, that is, the compound of interest and a calibrant. Thus, an analyte concentration can be determined using a calibration compound at a known concentration. One particularly time-consuming step in the qNMR analysis of compound libraries is the manual integration of peaks. In this report is presented an automated method for performing this task without prior knowledge of compound structures and by using an external calibration spectrum. The script for automated integration is fast and adaptable to large-scale data sets, eliminating the need for manual integration in ~80% of the cases.

  1. Quality assessment and analysis of Biogen Idec compound library.

    PubMed

    Bowes, Scott; Sun, Dongyu; Kaffashan, Azita; Zeng, Chenhui; Chuaqui, Claudio; Hronowski, Xiaoping; Buko, Alex; Zhang, Xin; Josiah, Serene

    2006-10-01

    A subset of the compound repository for lead identification at Biogen Idec was characterized for its chemical stability over a 3-year period. Compounds were stored at 4 degrees C as 10 mM DMSO stocks, and a small subset of compounds was stored as lyophilized dry films. Compound integrity of 470 discrete compounds (Compound Set I) and 1917 combinatorial chemistry-derived compounds (Compound Set II) was evaluated by liquid chromatography/mass spectrometry from the time of acquisition into the library collection and after 3 years of storage. Loss of compound integrity over the 3 years of storage was observed across the 2 subsets tested. Of Compound Set I, 63% of samples retained > 80% purity, whereas 57% of samples from Compound Set II had purity greater than 60%. The stability of the lyophilized samples was superior to the samples stored as DMSO solution. Although storage at 4 degrees C as DMSO solution was adequate for the majority of compounds, the authors observed and quantified the level of degradation within the compound collection. Their study provides general insight into compound storage and selection of library subsets for future lead identification activities.

  2. Structure-Based Virtual Screening of Commercially Available Compound Libraries.

    PubMed

    Kireev, Dmitri

    2016-01-01

    Virtual screening (VS) is an efficient hit-finding tool. Its distinctive strength is that it allows one to screen compound libraries that are not available in the lab. Moreover, structure-based (SB) VS also enables an understanding of how the hit compounds bind the protein target, thus laying ground work for the rational hit-to-lead progression. SBVS requires a very limited experimental effort and is particularly well suited for academic labs and small biotech companies that, unlike pharmaceutical companies, do not have physical access to quality small-molecule libraries. Here, we describe SBVS of commercial compound libraries for Mer kinase inhibitors. The screening protocol relies on the docking algorithm Glide complemented by a post-docking filter based on structural protein-ligand interaction fingerprints (SPLIF).

  3. Designing Multi-target Compound Libraries with Gaussian Process Models.

    PubMed

    Bieler, Michael; Reutlinger, Michael; Rodrigues, Tiago; Schneider, Petra; Kriegl, Jan M; Schneider, Gisbert

    2016-05-01

    We present the application of machine learning models to selecting G protein-coupled receptor (GPCR)-focused compound libraries. The library design process was realized by ant colony optimization. A proprietary Boehringer-Ingelheim reference set consisting of 3519 compounds tested in dose-response assays at 11 GPCR targets served as training data for machine learning and activity prediction. We compared the usability of the proprietary data with a public data set from ChEMBL. Gaussian process models were trained to prioritize compounds from a virtual combinatorial library. We obtained meaningful models for three of the targets (5-HT2c , MCH, A1), which were experimentally confirmed for 12 of 15 selected and synthesized or purchased compounds. Overall, the models trained on the public data predicted the observed assay results more accurately. The results of this study motivate the use of Gaussian process regression on public data for virtual screening and target-focused compound library design. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

  4. Combinatorial Libraries of Bis-Heterocyclic Compounds with Skeletal Diversity

    PubMed Central

    Soural, Miroslav; Bouillon, Isabelle; Krchňák, Viktor

    2009-01-01

    Combinatorial solid-phase synthesis of bis-heterocyclic compounds, characterized by the presence of two heterocyclic cores connected by a spacer of variable length/structure, provided structurally heterogeneous libraries with skeletal diversity. Both heterocyclic rings were assembled on resin in a combinatorial fashion. PMID:18811208

  5. Antioxidant-prooxidant properties of a new organoselenium compound library.

    PubMed

    Plano, Daniel; Baquedano, Ylenia; Ibáñez, Elena; Jiménez, Iosu; Palop, Juan Antonio; Spallholz, Julian E; Sanmartín, Carmen

    2010-10-21

    The present study describes the biological evaluation of a library of 59 organo-selenium compounds as superoxide (O₂⁻) generators and cytotoxic agents in human prostate cancer cells (PC-3) and in breast adenocarcinoma (MCF-7). In order to corroborate that the biological activity for selenium compounds depends on the chemical form, a broad structural variety is presented. These structures include selenocyanates, diselenides, selenoalkyl functional moieties and eight newly synthesized symmetrically substituted dithioselenites and selenylureas. Eleven of the derivatives tested showed high levels of superoxide generation in vitro via oxidation of reduced glutathione (GSH) and nine of them were more catalytic than the reference compound, diselenodipropionic acid. Eighteen of the library compounds inhibited cell growth more than or similar to reference chemotherapeutic drugs in PC-3 and eleven were more potent cytotoxic agents than etoposide in the MCF-7 cell line. Considering both parameters (superoxide generation and cell cytotoxicity) compounds B1, C6 and C9 displayed the best therapeutic profiles. Considering that many diselenide compounds can generate superoxide (O₂⁻) in vitro via oxidation of GSH and other thiols, the analogue B1, that contains a diselenide moiety, was selected for a preliminary mechanistic investigation, which revealed that B1 has apoptogenic effects similar to camptothecin mediated by reactive oxygen species (ROS) in lymphocytic leukemia cells (CCRF-CEM) and affected the MCF-7 cell-cycle in G₂/M and S-phases.

  6. The Joint European Compound Library: boosting precompetitive research.

    PubMed

    Besnard, Jérémy; Jones, Philip S; Hopkins, Andrew L; Pannifer, Andrew D

    2015-02-01

    The Joint European Compound Library (JECL) is a new high-throughput screening collection aimed at driving precompetitive drug discovery and target validation. The JECL has been established with a core of over 321,000 compounds from the proprietary collections of seven pharmaceutical companies and will expand to around 500,000 compounds. Here, we analyse the physicochemical profile and chemical diversity of the core collection, showing that the collection is diverse and has a broad spectrum of predicted biological activity. We also describe a model for sharing compound information from multiple proprietary collections, enabling diversity and quality analysis without disclosing structures. The JECL is available for screening at no cost to European academic laboratories and SMEs through the IMI European Lead Factory (http://www.europeanleadfactory.eu/).

  7. GPU accelerated chemical similarity calculation for compound library comparison.

    PubMed

    Ma, Chao; Wang, Lirong; Xie, Xiang-Qun

    2011-07-25

    Chemical similarity calculation plays an important role in compound library design, virtual screening, and "lead" optimization. In this manuscript, we present a novel GPU-accelerated algorithm for all-vs-all Tanimoto matrix calculation and nearest neighbor search. By taking advantage of multicore GPU architecture and CUDA parallel programming technology, the algorithm is up to 39 times superior to the existing commercial software that runs on CPUs. Because of the utilization of intrinsic GPU instructions, this approach is nearly 10 times faster than existing GPU-accelerated sparse vector algorithm, when Unity fingerprints are used for Tanimoto calculation. The GPU program that implements this new method takes about 20 min to complete the calculation of Tanimoto coefficients between 32 M PubChem compounds and 10K Active Probes compounds, i.e., 324G Tanimoto coefficients, on a 128-CUDA-core GPU.

  8. A hierarchical clustering approach for large compound libraries.

    PubMed

    Böcker, Alexander; Derksen, Swetlana; Schmidt, Elena; Teckentrup, Andreas; Schneider, Gisbert

    2005-01-01

    A modified version of the k-means clustering algorithm was developed that is able to analyze large compound libraries. A distance threshold determined by plotting the sum of radii of leaf clusters was used as a termination criterion for the clustering process. Hierarchical trees were constructed that can be used to obtain an overview of the data distribution and inherent cluster structure. The approach is also applicable to ligand-based virtual screening with the aim to generate preferred screening collections or focused compound libraries. Retrospective analysis of two activity classes was performed: inhibitors of caspase 1 [interleukin 1 (IL1) cleaving enzyme, ICE] and glucocorticoid receptor ligands. The MDL Drug Data Report (MDDR) and Collection of Bioactive Reference Analogues (COBRA) databases served as the compound pool, for which binary trees were produced. Molecules were encoded by all Molecular Operating Environment 2D descriptors and topological pharmacophore atom types. Individual clusters were assessed for their purity and enrichment of actives belonging to the two ligand classes. Significant enrichment was observed in individual branches of the cluster tree. After clustering a combined database of MDDR, COBRA, and the SPECS catalog, it was possible to retrieve MDDR ICE inhibitors with new scaffolds using COBRA ICE inhibitors as seeds. A Java implementation of the clustering method is available via the Internet (http://www.modlab.de).

  9. High-throughput purification of single compounds and libraries.

    PubMed

    Schaffrath, Mathias; von Roedern, Erich; Hamley, Peter; Stilz, Hans Ulrich

    2005-01-01

    The need for increasing productivity in medicinal chemistry and associated improvements in automated synthesis technologies for compound library production during the past few years have resulted in a major challenge for compound purification technology and its organization. To meet this challenge, we have recently set up three full-service chromatography units with the aid of in-house engineers, different HPLC suppliers, and several companies specializing in custom laboratory automation technologies. Our goal was to combine high-throughput purification with the high attention to detail which would be afforded by a dedicated purification service. The resulting final purification laboratory can purify up to 1000 compounds/week in amounts ranging from 5 to 300 mg, whereas the two service intermediate purification units take 100 samples per week from 0.3 to 100 g. The technologies consist of normal-phase and reversed-phase chromatography, robotic fraction pooling and reformatting, a bottling system, an automated external solvent supply and removal system, and a customized, high-capacity freeze-dryer. All work processes are linked by an electronic sample registration and tracking system.

  10. Leads for antitubercular compounds from kinase inhibitor library screens.

    PubMed

    Magnet, Sophie; Hartkoorn, Ruben C; Székely, Rita; Pató, János; Triccas, James A; Schneider, Patricia; Szántai-Kis, Csaba; Orfi, László; Chambon, Marc; Banfi, Damiano; Bueno, Manuel; Turcatti, Gerardo; Kéri, György; Cole, Stewart T

    2010-11-01

    Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find antimycobacterial scaffolds, we screened a kinase inhibitor library of more than 12,000 compounds using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and a target-based assay with the protein kinase PknA. Seventeen "hits" came from the whole cell-based screening approach, from which three displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10μM and were non-mutagenic and non-cytotoxic. Two of these hits were specific for M. tuberculosis versus C. glutamicum and none of them was found to inhibit the essential serine/threonine protein kinases, PknA and PknB present in both bacteria. One of the most active hits, VI-18469, had a benzoquinoxaline pharmacophore while another, VI-9376, is structurally related to a new class of antimycobacterial agents, the benzothiazinones (BTZ). Like the BTZ, VI-9376 was shown to act on the essential enzyme decaprenylphosphoryl-β-D-ribose 2'-epimerase, DprE1, required for arabinan synthesis.

  11. How enhanced molecular ions in Cold EI improve compound identification by the NIST library.

    PubMed

    Alon, Tal; Amirav, Aviv

    2015-12-15

    Library-based compound identification with electron ionization (EI) mass spectrometry (MS) is a well-established identification method which provides the names and structures of sample compounds up to the isomer level. The library (such as NIST) search algorithm compares different EI mass spectra in the library's database with the measured EI mass spectrum, assigning each of them a similarity score called 'Match' and an overall identification probability. Cold EI, electron ionization of vibrationally cold molecules in supersonic molecular beams, provides mass spectra with all the standard EI fragment ions combined with enhanced Molecular Ions and high-mass fragments. As a result, Cold EI mass spectra differ from those provided by standard EI and tend to yield lower matching scores. However, in most cases, library identification actually improves with Cold EI, as library identification probabilities for the correct library mass spectra increase, despite the lower matching factors. This research examined the way that enhanced molecular ion abundances affect library identification probability and the way that Cold EI mass spectra, which include enhanced molecular ions and high-mass fragment ions, typically improve library identification results. It involved several computer simulations, which incrementally modified the relative abundances of the various ions and analyzed the resulting mass spectra. The simulation results support previous measurements, showing that while enhanced molecular ion and high-mass fragment ions lower the matching factor of the correct library compound, the matching factors of the incorrect library candidates are lowered even more, resulting in a rise in the identification probability for the correct compound. This behavior which was previously observed by analyzing Cold EI mass spectra can be explained by the fact that high-mass ions, and especially the molecular ion, characterize a compound more than low-mass ions and therefore carries more

  12. Cyclopentitol as a scaffold for a natural product-like compound library for drug discovery.

    PubMed

    Padwal, Jalindar D; Filippov, Dmitri V; Narhe, Bharat D; Aertssen, Sjoerd; Beuving, Remmelt Jan; Benningshof, Jorg C J; van der Marel, Gijsbert A; Overkleeft, Herman S; van der Stelt, Mario

    2015-06-01

    A concise and efficient synthesis of cyclopentitols as a scaffold for a two-dimensional compound library for drug discovery is described. Starting from d-mannose, the key steps are Wittig olefination and ring-closing metathesis (RCM) followed by a [3,3]-sigmatropic Overmann rearrangement to form an sp(3)-rich, natural product-like scaffold from which a focused compound library with different functionalities is prepared.

  13. Specificity Profiling of Protein-Binding Domains Using One-Bead-One-Compound Peptide Libraries

    PubMed Central

    Kunys, Andrew R.; Lian, Wenlong; Pei, Dehua

    2013-01-01

    One-bead-one-compound (OBOC) libraries consist of structurally related compounds (e.g., peptides) covalently attached to a solid support, with each resin bead carrying a unique compound. OBOC libraries of high structural diversity can be rapidly synthesized and screened without the need of any special equipment and therefore can be employed in any chemical or biochemical laboratory. OBOC peptide libraries have been widely used to map the ligand specificity of proteins, to determine the substrate specificity of enzymes, and to develop inhibitors against macromolecular targets. They have proven particularly useful in profiling the binding specificity of protein modular domains (e.g., SH2 domains, BIR domains, and PDZ domains) and subsequently using the specificity information to predict the protein targets of these domains. The protocols outlined in this article describe the methodologies for synthesizing and screening OBOC peptide libraries against SH2 and PDZ domains and the related data analysis. PMID:23788558

  14. Identification of a Hit Series of Antileishmanial Compounds through the Use of Mixture-Based Libraries.

    PubMed

    Giulianotti, Marc A; Vesely, Brian A; Azhari, Ala; Souza, Ashley; LaVoi, Travis; Houghten, Richard A; Kyle, Dennis E; Leahy, James W

    2017-08-10

    From a screening campaign that included mixture-based libraries containing more than 6 million compounds, a lead series of bis-cyclic guanidines was identified as the most promising. Lead optimization resulted in the identification of potent (IC50 < 500 nM) and selective compounds within this series as well as potent and selective monoguanidines.

  15. Monitoring of HTS Compound Library Quality via a High-Resolution Image Acquisition and Processing Instrument

    PubMed Central

    Baillargeon, Pierre; Scampavia, Louis; Einsteder, Ross

    2011-01-01

    This report presents the high-resolution image acquisition and processing instrument for compound management applications (HIAPI-CM). The HIAPI-CM combines imaging spectroscopy and machine vision analysis to perform rapid assessment of HTS compound library quality. It has been customized to detect and classify typical artifacts found in HTS compound library microtiter plates (MTPs). These artifacts include: (a) insufficient volume of liquid compound sample, (b) compound precipitation, and (c) colored compounds that interfere with HTS assay detection format readout. The HIAPI-CM is also configured to automatically query & compare its analysis results to data stored in a LIMS or corporate database, aiding in the detection of compound registration errors. To demonstrate its capabilities, several compound plates (n =5760 wells total) containing different artifacts were measured via automated HIAPI-CM analysis, and results compared to those obtained by manual (visual) inspection. In all cases, the instrument demonstrated high fidelity (99.8% empty wells; 100.1% filled wells; 94.4% for partially filled wells; 94.0% for wells containing colored compounds), and in the case of precipitate detection, the HIAPI-CM results significantly exceeded the fidelity of visual observations (220.0%). As described, the HIAPI-CM allows for noninvasive, nondestructive MTP assessment with a diagnostic throughput of about one minute per plate, reducing analytical expenses and improving the quality and stewardship of HTS compound libraries. PMID:21609702

  16. Synthesis and preliminary biological evaluation of a compound library of triazolylcyclitols.

    PubMed

    Carrau, Gonzalo; Drewes, Carine C; Shimada, Ana Lúcia B; Bertucci, Ana; Farsky, Sandra H P; Stefani, Helio A; Gonzalez, David

    2013-07-15

    A small library of compounds was prepared by a combination of toluene dioxygenase (TDO)-catalyzed enzymatic dihydroxylation and copper(I)-catalyzed Hüisgen cycloaddition. Some compounds were obtained by coupling an alkyne and a conduritol derivative, while more complex structures were obtained by a double Hüisgen reaction of a dialkyne and two molecules of the cyclitol. The compounds were fully characterized and subjected to preliminary biological screening.

  17. Synthesis, screening, and sequencing of cysteine-rich one-bead one-compound peptide libraries.

    PubMed

    Juskowiak, Gary L; McGee, Christopher J; Greaves, John; Van Vranken, David L

    2008-01-01

    Cysteine-rich peptides are valued as tags for biarsenical fluorophores and as environmentally important reagents for binding toxic heavy metals. Due to the inherent difficulties created by cysteine, the power of one-bead one-compound (OBOC) libraries has never been applied to the discovery of short cysteine-rich peptides. We have developed the first method for the synthesis, screening, and sequencing of cysteine-rich OBOC peptide libraries. First, we synthesized a heavily biased cysteine-rich OBOC library, incorporating 50% cysteine at each position (Ac-X8-KM-TentaGel). Then, we developed conditions for cysteine alkylation, cyanogen bromide cleavage, and direct MS/MS sequencing of that library at the single bead level. The sequencing efficiency of this library was comparable to a traditional cysteine-free library. To validate screening of cysteine-rich OBOC libraries, we reacted a library with the biarsenical FlAsH and identified beads bearing the known biarsenical-binding motif (CCXXCC). These results enable OBOC libraries to be used in high-throughput discovery of cysteine-rich peptides for protein tagging, environmental remediation of metal contaminants, or cysteine-rich pharmaceuticals.

  18. Direct comparison of linear and macrocyclic compound libraries as a source of protein ligands.

    PubMed

    Gao, Yu; Kodadek, Thomas

    2015-03-09

    There has been much discussion of the potential desirability of macrocyclic molecules for the development of tool compounds and drug leads. But there is little experimental data comparing otherwise equivalent macrocyclic and linear compound libraries as a source of protein ligands. In this Letter, we probe this point in the context of peptoid libraries. Bead-displayed libraries of macrocyclic and linear peptoids containing four variable positions and 0-2 fixed residues, to vary the ring size, were screened against streptavidin and the affinity of every hit for the target was measured. The data show that macrocyclization is advantageous, but only when the ring contains 17 atoms, not 20 or 23 atoms. This technology will be useful for conducting direct comparisons between many different types of chemical libraries to determine their relative utility as a source of protein ligands.

  19. Self-organizing maps in drug discovery: compound library design, scaffold-hopping, repurposing.

    PubMed

    Schneider, P; Tanrikulu, Y; Schneider, G

    2009-01-01

    High-throughput screening campaigns are fuelled not only by corporate or "maximally diverse" compound collections, but increasingly accompanied by target- or bioactivity-focused selections of screening compounds. Computer-assisted library design methods aid in the compilation of focused molecule libraries. A prerequisite for application of any such computational approach is the definition of a reference set and a molecular similarity metric, based on which compound clustering and iterative virtual screening are performed. In this context the self-organizing map (SOM, Kohonen network) and variations thereof have found widespread application. SOMs cover such diverse fields of drug discovery as screening library design, scaffold-hopping, and repurposing. Here we present the concept of the SOM technique along with recent case studies. Advantages, limitations and potential future applications are critically discussed.

  20. Rapid lead discovery through iterative screening of one bead one compound libraries.

    PubMed

    Gao, Yu; Amar, Sabrina; Pahwa, Sonia; Fields, Gregg; Kodadek, Thomas

    2015-01-12

    Primary hits that arise from screening one bead one compound (OBOC) libraries against a target of interest rarely have high potency. However, there has been little work focused on the development of an efficient workflow for primary hit improvement. In this study, we show that by characterizing the binding constants for all of the hits that arise from a screen, structure-activity relationship (SAR) data can be obtained to inform the design of "derivative libraries" of a primary hit that can then be screened under more demanding conditions to obtain improved compounds. Here, we demonstrate the rapid improvement of a primary hit against matrix metalloproteinase-14 using this approach.

  1. Search for new compounds from Kitasato microbial library by physicochemical screening.

    PubMed

    Nakashima, Takuji; Takahashi, Yōko; Ōmura, Satoshi

    2017-06-15

    The Ōmura research group of the Kitasato Institute has isolated multiple microorganisms over a period of five decades. The resulting collection comprises a broad spectrum of microbes, including strains producing novel and diverse compounds with biological activities. A bioassay-guided fractionation of microbial culture broths has been employed to screen the microbial collection for compounds with new biological activities. And numerous novel natural products have been discovered among the microbial metabolites produced by members of the collection. However, dereplication of already known compounds and their potential analogs is a vital part of the discovery process of new microbial natural products. Recently, it has become easy to acquire the ultraviolet (UV) and mass spectrometry (MS) spectra of many single components of microbial culture broths in combination with high-performance liquid chromatography. To achieve most effective utilization of our microbial library, new compounds from microbial culture broths were investigated by employing an approach based on the physico-chemical properties using spectral analyses such as UV and MS and color reaction, collectively designated as physicochemical (PC) screening. As a result of physicochemical screening, many new compounds were identified among the secondary metabolites of fresh isolated rare actinomycetes and Streptomyces spp. preserved for a long time as producer of biological compounds. In this review, we introduce the Kitasato microbial library and the new compounds discovered from the library by PC screening. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Target Profile Prediction and Practical Evaluation of a Biginelli-Type Dihydropyrimidine Compound Library

    PubMed Central

    Schneider, Petra; Stutz, Katharina; Kasper, Ladina; Haller, Sarah; Reutlinger, Michael; Reisen, Felix; Geppert, Tim; Schneider, Gisbert

    2011-01-01

    We present a self-organizing map (SOM) approach to predicting macromolecular targets for combinatorial compound libraries. The aim was to study the usefulness of the SOM in combination with a topological pharmacophore representation (CATS) for selecting biologically active compounds from a virtual combinatorial compound collection, taking the multi-component Biginelli dihydropyrimidine reaction as an example. We synthesized a candidate compound from this library, for which the SOM model suggested inhibitory activity against cyclin-dependent kinase 2 (CDK2) and other kinases. The prediction was confirmed in an in vitro panel assay comprising 48 human kinases. We conclude that the computational technique may be used for ligand-based in silico pharmacology studies, off-target prediction, and drug re-purposing, thereby complementing receptor-based approaches.

  3. Comparative analysis of machine learning methods in ligand-based virtual screening of large compound libraries.

    PubMed

    Ma, Xiao H; Jia, Jia; Zhu, Feng; Xue, Ying; Li, Ze R; Chen, Yu Z

    2009-05-01

    Machine learning methods have been explored as ligand-based virtual screening tools for facilitating drug lead discovery. These methods predict compounds of specific pharmacodynamic, pharmacokinetic or toxicological properties based on their structure-derived structural and physicochemical properties. Increasing attention has been directed at these methods because of their capability in predicting compounds of diverse structures and complex structure-activity relationships without requiring the knowledge of target 3D structure. This article reviews current progresses in using machine learning methods for virtual screening of pharmacodynamically active compounds from large compound libraries, and analyzes and compares the reported performances of machine learning tools with those of structure-based and other ligand-based (such as pharmacophore and clustering) virtual screening methods. The feasibility to improve the performance of machine learning methods in screening large libraries is discussed.

  4. Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries.

    PubMed

    Cordier, Christopher; Morton, Daniel; Murrison, Sarah; Nelson, Adam; O'Leary-Steele, Catherine

    2008-08-01

    The purpose of diversity-oriented synthesis is to drive the discovery of small molecules with previously unknown biological functions. Natural products necessarily populate biologically relevant chemical space, since they bind both their biosynthetic enzymes and their target macromolecules. Natural product families are, therefore, libraries of pre-validated, functionally diverse structures in which individual compounds selectively modulate unrelated macromolecular targets. This review describes examples of diversity-oriented syntheses which have, to some extent, been inspired by the structures of natural products. Particular emphasis is placed on innovations that allow the synthesis of compound libraries that, like natural products, are skeletally diverse. Mimicking the broad structural features of natural products may allow the discovery of compounds that modulate the functions of macromolecules for which ligands are not known. The ability of innovations in diversity-oriented synthesis to deliver such compounds is critically assessed.

  5. Monitoring of HTS compound library quality via a high-resolution image acquisition and processing instrument.

    PubMed

    Baillargeon, Pierre; Scampavia, Louis; Einsteder, Ross; Hodder, Peter

    2011-06-01

    This report presents the high-resolution image acquisition and processing instrument for compound management applications (HIAPI-CM). The HIAPI-CM combines imaging spectroscopy and machine-vision analysis to perform rapid assessment of high-throughput screening (HTS) compound library quality. It has been customized to detect and classify typical artifacts found in HTS compound library microtiter plates (MTPs). These artifacts include (1) insufficient volume of liquid compound sample, (2) compound precipitation, and (3) colored compounds that interfere with HTS assay detection format readout. The HIAPI-CM is also configured to automatically query and compare its analysis results to data stored in a LIMS or corporate database, aiding in the detection of compound registration errors. To demonstrate its capabilities, several compound plates (n=5760 wells total) containing different artifacts were measured via automated HIAPI-CM analysis, and results compared with those obtained by manual (visual) inspection. In all cases, the instrument demonstrated high fidelity (99.8% empty wells; 100.1% filled wells; 94.4% for partially filled wells; 94.0% for wells containing colored compounds), and in the case of precipitate detection, the HIAPI-CM results significantly exceeded the fidelity of visual observations (220.0%). As described, the HIAPI-CM allows for noninvasive, nondestructive MTP assessment with a diagnostic throughput of about 1min per plate, reducing analytical expenses and improving the quality and stewardship of HTS compound libraries. Copyright © 2011 Society for Laboratory Automation and Screening. Published by Elsevier Inc. All rights reserved.

  6. Nonlinear dimensionality reduction and mapping of compound libraries for drug discovery.

    PubMed

    Reutlinger, Michael; Schneider, Gisbert

    2012-04-01

    Visualization of 'chemical space' and compound distributions has received much attraction by medicinal chemists as it may help to intuitively comprehend pharmaceutically relevant molecular features. It has been realized that for meaningful feature extraction from complex multivariate chemical data, such as compound libraries represented by many molecular descriptors, nonlinear projection techniques are required. Recent advances in machine-learning and artificial intelligence have resulted in a transfer of such methods to chemistry. We provide an overview of prominent visualization methods based on nonlinear dimensionality reduction, and highlight applications in drug discovery. Emphasis is on neural network techniques, kernel methods and stochastic embedding approaches, which have been successfully used for ligand-based virtual screening, SAR landscape analysis, combinatorial library design, and screening compound selection.

  7. Template-based combinatorial enumeration of virtual compound libraries for lipids.

    PubMed

    Sud, Manish; Fahy, Eoin; Subramaniam, Shankar

    2012-09-25

    A variety of software packages are available for the combinatorial enumeration of virtual libraries for small molecules, starting from specifications of core scaffolds with attachments points and lists of R-groups as SMILES or SD files. Although SD files include atomic coordinates for core scaffolds and R-groups, it is not possible to control 2-dimensional (2D) layout of the enumerated structures generated for virtual compound libraries because different packages generate different 2D representations for the same structure. We have developed a software package called LipidMapsTools for the template-based combinatorial enumeration of virtual compound libraries for lipids. Virtual libraries are enumerated for the specified lipid abbreviations using matching lists of pre-defined templates and chain abbreviations, instead of core scaffolds and lists of R-groups provided by the user. 2D structures of the enumerated lipids are drawn in a specific and consistent fashion adhering to the framework for representing lipid structures proposed by the LIPID MAPS consortium. LipidMapsTools is lightweight, relatively fast and contains no external dependencies. It is an open source package and freely available under the terms of the modified BSD license.

  8. A virtual screening method for prediction of the HERG potassium channel liability of compound libraries.

    PubMed

    Roche, Olivier; Trube, Gerhard; Zuegge, Jochen; Pflimlin, Pascal; Alanine, Alexander; Schneider, Gisbert

    2002-05-03

    A computer-based method has been developed for prediction of the hERG (human ether-à-go-go related gene) K(+)-channel affinity of low molecular weight compounds. hERG channel blockage is a major concern in drug design, as such blocking agents can cause sudden cardiac death. Various techniques were applied to finding appropriate molecular descriptors for modeling structure-activity relationships: substructure analysis, self-organizing maps (SOM), principal component analysis (PCA), partial least squares fitting (PLS), and supervised neural networks. The most accurate prediction system was based on an artificial neural network. In a validation study, 93 % of the nonblocking agents and 71 % of the hERG channel blockers were correctly classified. This virtual screening method can be used for general compound-library shaping and combinatorial library design.

  9. Aminodeoxychorismate synthase inhibitors from one-bead one-compound combinatorial libraries: "staged" inhibitor design.

    PubMed

    Dixon, Seth; Ziebart, Kristin T; He, Ze; Jeddeloh, Melissa; Yoo, Choong Leol; Wang, Xiaobing; Lehman, Alan; Lam, Kit S; Toney, Michael D; Kurth, Mark J

    2006-12-14

    4-Amino-4-deoxychorismate synthase (ADCS) catalyzes the first step in the conversion of chorismate into p-aminobenzoate, which is incorporated into folic acid. We aim to discover compounds that inhibit ADCS and serve as leads for a new class of antimicrobial compounds. This report presents (1) synthesis of a mass-tag encoded library based on a "staged" design, (2) massively parallel fluorescence-based on-bead screening, (3) rapid structural identification of hits, and (4) full kinetic analysis of ADCS. All inhibitors are competitive against chorismate and Mg(2+). The most potent ADCS inhibitor identified has a K(i) of 360 microM. We show that the combinatorial diversity elements add substantial binding affinity by interacting with residues outside of but proximal to the active site. The methods presented here constitute a paradigm for inhibitor discovery through active site targeting, enabled by rapid library synthesis, facile massively parallel screening, and straightforward hit identification.

  10. Identification of SQ609 as a lead compound from a library of dipiperidines.

    PubMed

    Bogatcheva, Elena; Hanrahan, Colleen; Nikonenko, Boris; de los Santos, Gladys; Reddy, Venkata; Chen, Ping; Barbosa, Francis; Einck, Leo; Nacy, Carol; Protopopova, Marina

    2011-09-15

    We recently reported that compounds created around a dipiperidine scaffold demonstrated activity against Mycobacterium tuberculosis (Mtb) (Bogatcheva, E.; Hanrahan, C.; Chen, P.; Gearhart, J.; Sacksteder, K.; Einck, L.; Nacy, C.; Protopopova, M. Bioorg. Med. Chem. Lett.2010, 20, 201). To optimize the dipiperidine compound series and to select a lead compound to advance into preclinical studies, we evaluated the structure-activity relationship (SAR) of our proprietary libraries. The (piperidin-4-ylmethyl)piperidine scaffold was an essential structural element required for antibacterial activity. Based on SAR, we synthesized a focused library of 313 new dipiperidines to delineate additional structural features responsible for antitubercular activity. Thirty new active compounds with MIC 10-20 μg/ml on Mtb were identified, but none was better than the original hits of this series, SQ609, SQ614, and SQ615. In Mtb-infected macrophages in vitro, SQ609 and SQ614 inhibited more than 90% of intracellular bacterial growth at 4 μg/ml; SQ615 was toxic to these cells. In mice infected with Mtb, weight loss was completely prevented by SQ609, but not SQ614, and SQ609 had a prolonged therapeutic effect, extended by 10-15 days, after cessation of therapy. Based on in vitro and in vivo antitubercular activity, SQ609 was identified as the best-in-class dipiperidine compound in the series. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Finding key members in compound libraries by analyzing networks of molecules assembled by structural similarity.

    PubMed

    Lepp, Zsolt; Huang, Chunfei; Okada, Takashi

    2009-11-01

    Characterization of chemical libraries is an essential task in everyday chemoinformatics practice. This study describes some potential uses of network visualization and analysis methods to identify distinguished members of compound libraries. Molecules were ordered into networks by their structural similarity defined by molecular fingerprints. Various properties of such networks were examined. It was shown, that the correlation methods used to calculate the similarity between two structures radically determined the topology of networks. From the same set of molecules, the Russel-Rao and the Baroni-Urbani methods created sparser and denser networks, respectively, than using the Tanimoto method. Central nodes, corresponding to central compounds in the libraries, were determined for some example data sets. It was shown by the case of adenosine A1, A2, and dual antagonists that the methods used to identify central nodes could be divided into two groups: (1) centrality methods, exemplified by the centroid centrality, which could pick up structures that were the most similar to the largest number of other molecules and (2) group, exemplified by betweenness centrality, that could identify molecules that had intermediate structures between some homogeneous subsets of the library. The latter method gave significantly higher ranks to dual adenosine antagonists, hinting the suitability of this measure to identify molecules with multiple activities. Some practical applications of the method for clustering of and sample selection from chemical libraries are presented. In the frame of the study, a Jchem plug-in has been developed to the Cytoscape network visualization software, which makes the visual observation of molecular networks more convenient. The plug-in is included in the Supporting Information of the article for free usage.

  12. Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries.

    PubMed

    Minond, Dmitriy; Saldanha, S Adrian; Subramaniam, Prem; Spaargaren, Michael; Spicer, Timothy; Fotsing, Joseph R; Weide, Timo; Fokin, Valery V; Sharpless, K Barry; Galleni, Moreno; Bebrone, Carine; Lassaux, Patricia; Hodder, Peter

    2009-07-15

    VIM-2 is an Ambler class B metallo-beta-lactamase (MBL) capable of hydrolyzing a broad-spectrum of beta-lactam antibiotics. Although the discovery and development of MBL inhibitors continue to be an area of active research, an array of potent, small molecule inhibitors is yet to be fully characterized for VIM-2. In the presented research, a compound library screening approach was used to identify and characterize VIM-2 inhibitors from a library of pharmacologically active compounds as well as a focused 'click' chemistry library. The four most potent VIM-2 inhibitors resulting from a VIM-2 screen were characterized by kinetic studies in order to determine K(i) and mechanism of enzyme inhibition. As a result, two previously described pharmacologic agents, mitoxantrone (1,4-dihydroxy-5,8-bis([2-([2-hydroxyethyl]amino)ethyl]amino)-9,10-anthracenedione) and 4-chloromercuribenzoic acid (pCMB) were found to be active, the former as a non-competitive inhibitor (K(i)=K(i)(')=1.5+/-0.2microM) and the latter as a slowly reversible or irreversible inhibitor. Additionally, two novel sulfonyl-triazole analogs from the click library were identified as potent, competitive VIM-2 inhibitors: N-((4-((but-3-ynyloxy)methyl)-1H-1,2,3-triazol-5-yl)methyl)-4-iodobenzenesulfonamide (1, K(i)=0.41+/-0.03microM) and 4-iodo-N-((4-(methoxymethyl)-1H-1,2,3-triazol-5-yl)methyl)benzenesulfonamide (2, K(i)=1.4+/-0.10microM). Mitoxantrone and pCMB were also found to potentiate imipenem efficacy in MIC and synergy assays employing Escherichia coli. Taken together, all four compounds represent useful chemical probes to further investigate mechanisms of VIM-2 inhibition in biochemical and microbiology-based assays.

  13. Identification of small molecule aggregators from large compound libraries by support vector machines.

    PubMed

    Rao, Hanbing; Li, Zerong; Li, Xiangyuan; Ma, Xiaohua; Ung, Choongyong; Li, Hu; Liu, Xianghui; Chen, Yuzong

    2010-03-01

    Small molecule aggregators non-specifically inhibit multiple unrelated proteins, rendering them therapeutically useless. They frequently appear as false hits and thus need to be eliminated in high-throughput screening campaigns. Computational methods have been explored for identifying aggregators, which have not been tested in screening large compound libraries. We used 1319 aggregators and 128,325 non-aggregators to develop a support vector machines (SVM) aggregator identification model, which was tested by four methods. The first is five fold cross-validation, which showed comparable aggregator and significantly improved non-aggregator identification rates against earlier studies. The second is the independent test of 17 aggregators discovered independently from the training aggregators, 71% of which were correctly identified. The third is retrospective screening of 13M PUBCHEM and 168K MDDR compounds, which predicted 97.9% and 98.7% of the PUBCHEM and MDDR compounds as non-aggregators. The fourth is retrospective screening of 5527 MDDR compounds similar to the known aggregators, 1.14% of which were predicted as aggregators. SVM showed slightly better overall performance against two other machine learning methods based on five fold cross-validation studies of the same settings. Molecular features of aggregation, extracted by a feature selection method, are consistent with published profiles. SVM showed substantial capability in identifying aggregators from large libraries at low false-hit rates. (c) 2009 Wiley Periodicals, Inc.

  14. Virtual screening of Abl inhibitors from large compound libraries by support vector machines.

    PubMed

    Liu, X H; Ma, X H; Tan, C Y; Jiang, Y Y; Go, M L; Low, B C; Chen, Y Z

    2009-09-01

    Abl promotes cancers by regulating cell morphogenesis, motility, growth, and survival. Successes of several marketed and clinical trial Abl inhibitors against leukemia and other cancers and appearances of reduced efficacies and drug resistances have led to significant interest in and efforts for developing new Abl inhibitors. In silico methods of pharmacophore, fragment, and molecular docking have been used in some of these efforts. It is desirable to explore other in silico methods capable of searching large compound libraries at high yields and reduced false-hit rates. We evaluated support vector machines (SVM) as a virtual screening tool for searching Abl inhibitors from large compound libraries. SVM trained and tested by 708 inhibitors and 65,494 putative noninhibitors correctly identified 84.4 to 92.3% inhibitors and 99.96 to 99.99% noninhibitors in 5-fold cross validation studies. SVM trained by 708 pre-2008 inhibitors and 65 494 putative noninhibitors correctly identified 50.5% of the 91 inhibitors reported since 2008 and predicted as inhibitors 29,072 (0.21%) of 13.56M PubChem, 659 (0.39%) of 168K MDDR, and 330 (5.0%) of 6638 MDDR compounds similar to the known inhibitors. SVM showed comparable yields and substantially reduced false-hit rates against two similarity based and another machine learning VS methods based on the same training and testing data sets and molecular descriptors. These suggest that SVM is capable of searching Abl inhibitors from large compound libraries at low false-hit rates.

  15. Library+

    ERIC Educational Resources Information Center

    Merrill, Alex

    2011-01-01

    This article discusses possible future directions for academic libraries in the post Web/Library 2.0 world. These possible directions include areas such as data literacy, linked data sets, and opportunities for libraries in support of digital humanities. The author provides a brief sketch of the background information regarding the topics and…

  16. FAF-Drugs3: a web server for compound property calculation and chemical library design.

    PubMed

    Lagorce, David; Sperandio, Olivier; Baell, Jonathan B; Miteva, Maria A; Villoutreix, Bruno O

    2015-07-01

    Drug attrition late in preclinical or clinical development is a serious economic problem in the field of drug discovery. These problems can be linked, in part, to the quality of the compound collections used during the hit generation stage and to the selection of compounds undergoing optimization. Here, we present FAF-Drugs3, a web server that can be used for drug discovery and chemical biology projects to help in preparing compound libraries and to assist decision-making during the hit selection/lead optimization phase. Since it was first described in 2006, FAF-Drugs has been significantly modified. The tool now applies an enhanced structure curation procedure, can filter or analyze molecules with user-defined or eight predefined physicochemical filters as well as with several simple ADMET (absorption, distribution, metabolism, excretion and toxicity) rules. In addition, compounds can be filtered using an updated list of 154 hand-curated structural alerts while Pan Assay Interference compounds (PAINS) and other, generally unwanted groups are also investigated. FAF-Drugs3 offers access to user-friendly html result pages and the possibility to download all computed data. The server requires as input an SDF file of the compounds; it is open to all users and can be accessed without registration at http://fafdrugs3.mti.univ-paris-diderot.fr.

  17. FAF-Drugs3: a web server for compound property calculation and chemical library design

    PubMed Central

    Lagorce, David; Sperandio, Olivier; Baell, Jonathan B.; Miteva, Maria A.; Villoutreix, Bruno O.

    2015-01-01

    Drug attrition late in preclinical or clinical development is a serious economic problem in the field of drug discovery. These problems can be linked, in part, to the quality of the compound collections used during the hit generation stage and to the selection of compounds undergoing optimization. Here, we present FAF-Drugs3, a web server that can be used for drug discovery and chemical biology projects to help in preparing compound libraries and to assist decision-making during the hit selection/lead optimization phase. Since it was first described in 2006, FAF-Drugs has been significantly modified. The tool now applies an enhanced structure curation procedure, can filter or analyze molecules with user-defined or eight predefined physicochemical filters as well as with several simple ADMET (absorption, distribution, metabolism, excretion and toxicity) rules. In addition, compounds can be filtered using an updated list of 154 hand-curated structural alerts while Pan Assay Interference compounds (PAINS) and other, generally unwanted groups are also investigated. FAF-Drugs3 offers access to user-friendly html result pages and the possibility to download all computed data. The server requires as input an SDF file of the compounds; it is open to all users and can be accessed without registration at http://fafdrugs3.mti.univ-paris-diderot.fr. PMID:25883137

  18. Development of CXCR4 modulators by virtual HTS of a novel amide-sulfamide compound library.

    PubMed

    Bai, Renren; Shi, Qi; Liang, Zhongxing; Yoon, Younghyoun; Han, Yiran; Feng, Amber; Liu, Shuangping; Oum, Yoonhyeun; Yun, C Chris; Shim, Hyunsuk

    2017-01-27

    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. Based on the designed parent framework, 30 prioritized amide-sulfamide structures were obtained after systemic filtering and docking screening. Twelve compounds were prepared from the top-30 list. Most synthesized compounds exhibited good to excellent binding affinity to CXCR4. Compounds Ig and Im demonstrated notable in vivo suppressive activity against xylene-induced mouse ear inflammation (with 56% and 54% inhibition). Western blot analyses revealed that Ig significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt. Moreover, Ig attenuated the amount of TNF-α secreted by pathogenic E. coli-infected macrophages. More importantly, Ig had no observable cytotoxicity. Our results demonstrated that FRESH virtual high throughput screening program of targeted chemical class could successfully find potent lead compounds, and the amide-sulfamide pharmacophore was a novel and effective framework blocking CXCR4 function.

  19. Lead selection of antiparasitic compounds from a focused library of benzenesulfonyl derivatives of heterocycles.

    PubMed

    Pagliero, Romina J; Kaiser, Marcel; Brun, Reto; Nieto, Marcelo J; Mazzieri, María R

    2017-09-01

    A library of 89 synthetic benzenesulfonyl derivatives of heterocycles with drug-like properties was assayed for in vitro antiparasitic activity and the results were added to our previously reported derivatives for a comprehensive SAR evaluation. Four compounds showed an IC50 between 0.25 and 3μM against Leishmania donovani and low cytotoxicity. Compound G{16} (1-(2,3,5,6-tetramethylphenylsulfonyl)-2-methylindoline), was particularly interesting with an IC50 similar to the reference drug miltefosine. Seven compounds showed an IC50 below 6µM against Trypanosoma cruzi, and three of them (E{3}, E{9} and G{3}) were identified as lead scaffolds for further optimization based on their activity-toxicity profile. Two promising structures (B{15} and G{15}) showed moderate inhibitory activity against Plasmodium falciparum. In general, the presence of a benzenesulfonyl moiety improves the antiparasitic activity of the heterocycles included in this study (with the exception of Trypanosoma brucei rhodesiense), validating the criteria used in the selection of the privileged structures and diversification used to generate this library. SAR analysis showed that the presence of lipophilic and electron withdrawing groups were favorable for the antiparasitic activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Rapid Lead Discovery Through Iterative Screening of One Bead One Compound Libraries

    PubMed Central

    2015-01-01

    Primary hits that arise from screening one bead one compound (OBOC) libraries against a target of interest rarely have high potency. However, there has been little work focused on the development of an efficient workflow for primary hit improvement. In this study, we show that by characterizing the binding constants for all of the hits that arise from a screen, structure–activity relationship (SAR) data can be obtained to inform the design of “derivative libraries” of a primary hit that can then be screened under more demanding conditions to obtain improved compounds. Here, we demonstrate the rapid improvement of a primary hit against matrix metalloproteinase-14 using this approach. PMID:25434974

  1. Discovery of novel SERCA inhibitors by virtual screening of a large compound library.

    PubMed

    Elam, Christopher; Lape, Michael; Deye, Joel; Zultowsky, Jodie; Stanton, David T; Paula, Stefan

    2011-05-01

    Two screening protocols based on recursive partitioning and computational ligand docking methodologies, respectively, were employed for virtual screens of a compound library with 345,000 entries for novel inhibitors of the enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA), a potential target for cancer chemotherapy. A total of 72 compounds that were predicted to be potential inhibitors of SERCA were tested in bioassays and 17 displayed inhibitory potencies at concentrations below 100 μM. The majority of these inhibitors were composed of two phenyl rings tethered to each other by a short link of one to three atoms. Putative interactions between SERCA and the inhibitors were identified by inspection of docking-predicted poses and some of the structural features required for effective SERCA inhibition were determined by analysis of the classification pattern employed by the recursive partitioning models.

  2. A molecular barcoded yeast ORF library enables mode-of-action analysis of bioactive compounds

    PubMed Central

    Gresham, David; Nishimura, Shinichi; Natarajan, Paramasivam; Koh, Judice L Y; Porter, Justin; Gray, Christopher A; Andersen, Raymond J; Giaever, Guri; Nislow, Corey; Andrews, Brenda; Botstein, David; Graham, Todd R; Yoshida, Minoru; Boone, Charles

    2013-01-01

    We present a yeast chemical-genomics approach designed to identify genes that when mutated confer drug resistance, thereby providing insight about the modes of action of compounds. We developed a molecular barcoded yeast open reading frame (MoBY-ORF) library in which each gene, controlled by its native promoter and terminator, is cloned into a centromere-based vector along with two unique oligonucleotide barcodes. The MoBY-ORF resource has numerous genetic and chemical-genetic applications, but here we focus on cloning wild-type versions of mutant drug-resistance genes using a complementation strategy and on simultaneously assaying the fitness of all transformants with barcode microarrays. The complementation cloning was validated by mutation detection using whole-genome yeast tiling microarrays, which identified unique polymorphisms associated with a drug-resistant mutant. We used the MoBY-ORF library to identify the genetic basis of several drug-resistant mutants and in this analysis discovered a new class of sterol-binding compounds. PMID:19349972

  3. Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum.

    PubMed

    Bertoldo, Jean Borges; Chiaradia-Delatorre, Louise Domeneghini; Mascarello, Alessandra; Leal, Paulo César; Cordeiro, Marlon Norberto Sechini; Nunes, Ricardo José; Sarduy, Emir Salas; Rosenthal, Philip Jon; Terenzi, Hernán

    2015-04-01

    Falcipain-2 (FP-2) is a key cysteine protease from the malaria parasite Plasmodium falciparum. Many previous studies have identified FP-2 inhibitors; however, none has yet met the criteria for an antimalarial drug candidate. In this work, we assayed an in-house library of non-peptidic organic compounds, including (E)-chalcones, (E)-N'-benzylidene-benzohydrazides and alkyl-esters of gallic acid, and assessed the activity toward FP-2 and their mechanisms of inhibition. The (E)-chalcones 48, 54 and 66 showed the lowest IC50 values (8.5 ± 0.8 µM, 9.5 ± 0.2 µM and 4.9 ± 1.3 µM, respectively). The best inhibitor (compound 66) demonstrated non-competitive inhibition, and using mass spectrometry and fluorescence spectroscopy assays, we suggest a potential allosteric site for the interaction of this compound, located between the catalytic site and the hemoglobin binding arm in FP-2. We combined structural biology tools and mass spectrometry to characterize the inhibition mechanisms of novel compounds targeting FP-2.

  4. Drug-likeness and increased hydrophobicity of commercially available compound libraries for drug screening.

    PubMed

    Zuegg, Johannes; Cooper, Matthew A

    2012-01-01

    Most drug discovery programs today originate by selection of 'hit' molecules resulting from assays against large compound screening libraries. The chemical space in which these hits reside has implications for its biological activity in vivo and likelihood of progression to a drug candidate. We have created a database of commercially available screening compounds and natural products in order to analyse the drug- and lead-likeness of commercial screening compounds and compare them with i) orally administered drugs, ii) non-orally administered drugs, and iii) compounds with significant biological activity but unspecified or not yet determined route of administration from the public databases DrugBank and ChEMBL. The data set contained 15.5 million entries from 102 vendors, which resulted in just over 8 million unique chemical structures. We review these data for current drug/lead-likeness, then utilise substructure-based filters for promiscuity and unwanted groups, and finally compare chemical properties for structures within the different sub-sets. While the majority of the commercial compounds satisfy various drug-likeness rules, they show a larger molecular weight and higher hydrophobicity compared to orally available drugs, with generally higher aromaticity and lower solubility. This 'right shift' of chemical properties has also been found in the majority of the compounds with significant biological activity in ChEMBL, reflecting a common trend in current drug discovery, towards larger, more hydrophobic compounds and fewer drug-like compounds. In particular, successful drugs were found to possess much lower median logD values than those found for compound collections. In addition, commercial compounds show a quite narrow distribution in molecular weight, with a median absolute deviation of only 78 Da around a median of 387 Da. For high-throughput screening a highly stringent combination of several lead-likeness and substructure filters against unwanted groups

  5. Ligand efficiency based approach for efficient virtual screening of compound libraries.

    PubMed

    Ke, Yi-Yu; Coumar, Mohane Selvaraj; Shiao, Hui-Yi; Wang, Wen-Chieh; Chen, Chieh-Wen; Song, Jen-Shin; Chen, Chun-Hwa; Lin, Wen-Hsing; Wu, Szu-Huei; Hsu, John T A; Chang, Chung-Ming; Hsieh, Hsing-Pang

    2014-08-18

    Here we report for the first time the use of fit quality (FQ), a ligand efficiency (LE) based measure for virtual screening (VS) of compound libraries. The LE based VS protocol was used to screen an in-house database of 125,000 compounds to identify aurora kinase A inhibitors. First, 20 known aurora kinase inhibitors were docked to aurora kinase A crystal structure (PDB ID: 2W1C); and the conformations of docked ligand were used to create a pharmacophore (PH) model. The PH model was used to screen the database compounds, and rank (PH rank) them based on the predicted IC50 values. Next, LE_Scale, a weight-dependant LE function, was derived from 294 known aurora kinase inhibitors. Using the fit quality (FQ = LE/LE_Scale) score derived from the LE_Scale function, the database compounds were reranked (PH_FQ rank) and the top 151 (0.12% of database) compounds were assessed for aurora kinase A inhibition biochemically. This VS protocol led to the identification of 7 novel hits, with compound 5 showing aurora kinase A IC50 = 1.29 μM. Furthermore, testing of 5 against a panel of 31 kinase reveals that it is selective toward aurora kinase A & B, with <50% inhibition for other kinases at 10 μM concentrations and is a suitable candidate for further development. Incorporation of FQ score in the VS protocol not only helped identify a novel aurora kinase inhibitor, 5, but also increased the hit rate of the VS protocol by improving the enrichment factor (EF) for FQ based screening (EF = 828), compared to PH based screening (EF = 237) alone. The LE based VS protocol disclosed here could be applied to other targets for hit identification in an efficient manner.

  6. Toward designing drug-like libraries: a novel computational approach for prediction of drug feasibility of compounds.

    PubMed

    Wang, J; Ramnarayan, K

    1999-01-01

    Prediction of the degree of drug-like character in small molecules is of great industrial interest. The major barrier, however, is the lack of a definition for drug-like character. We used the concept of the multilevel chemical compatibility (MLCC) between a compound and a drug library as a measure of the drug-like character of a compound. The rationale is that the local chemical environment of each atom or group of atoms in a compound largely contributes to the stability, toxicity, and metabolism in vivo. A systematic comparison of the local environments within a compound and those within the existing drugs provides a basis for determining whether and how much a compound is drug-like. We applied the MLCC calculations to four test sets: top selling drugs, compounds under biological testing prior to the preclinical test, anticancer drugs, and compounds known to have poor drug-like character. The following conclusions were obtained: (1) A convergent number of unique local structure types were found in the analysis of the library of the existing drugs. It suggests that the current drug library contains about 80% of all the viable types; therefore, discovery of a drug with new local structures is only an event of relatively small probability. (2) The method is highly selective in discerning drug-like compounds: most of the top drugs are predicted to be drug-like, about one-quarter of the biological testing compounds are drug-like, and about one-fifth of the anticancer drugs are drug-like. (3) The method also correctly predicted that none of the known problematic compounds are drug-like. (4) The method is fast enough for computational screening of virtual combinatorial chemistry libraries and databases of available compounds.

  7. Antiviral Compounds Discovered by Virtual Screening of Small–Molecule Libraries against Dengue Virus E Protein

    PubMed Central

    Zhou, Zhigang; Khaliq, Mansoora; Suk, Jae-Eun; Patkar, Chinmay; Li, Long; Kuhn, Richard J.; Post, Carol Beth

    2009-01-01

    Infection by the mosquito-borne dengue virus causes dengue fever and the sometimes fatal dengue hemorrhagic fever. The increasing number of dengue infections per year suggests that the virus is becoming more virulent and its transmission is expanding. Nevertheless, no effective treatment for dengue infection currently exists. In a search for antiviral agents effective against dengue virus, we investigated the potential of targeting a structural protein site rather than an enzymatic one. Using this approach, we now report the discovery of a small molecule ligand that inhibits viral growth. Our results also provide the first evidence that the binding site, a pocket located at the hinge between domains 1 and 2 of the envelope protein (E protein) on the virus surface, is a valid target for antiviral therapy. Ligand candidates were identified from libraries of ∼142,000 compounds using a computational high-throughput screening protocol targeting this pocket of the E protein. Cell-based assays were conducted on 23 top-ranked compounds. Among four with good antiviral activity profiles, the compound P02 was found to inhibit viral reproduction at micromolar concentrations. Using saturation transfer difference NMR spectroscopy, we also show that the compound binds virus and competes for binding E protein with the known ligand N-octyl-β-d-glucoside. Together, the results are consistent with an inhibition mechanism against maturation or host-cell entry mediated by ligand binding to the E-protein pocket. P02 is a promising lead compound for future development of an effective treatment against dengue virus and related flaviviruses. PMID:19053243

  8. Molecular descriptor data explain market prices of a large commercial chemical compound library

    NASA Astrophysics Data System (ADS)

    Polanski, Jaroslaw; Kucia, Urszula; Duszkiewicz, Roksana; Kurczyk, Agata; Magdziarz, Tomasz; Gasteiger, Johann

    2016-06-01

    The relationship between the structure and a property of a chemical compound is an essential concept in chemistry guiding, for example, drug design. Actually, however, we need economic considerations to fully understand the fate of drugs on the market. We are performing here for the first time the exploration of quantitative structure-economy relationships (QSER) for a large dataset of a commercial building block library of over 2.2 million chemicals. This investigation provided molecular statistics that shows that on average what we are paying for is the quantity of matter. On the other side, the influence of synthetic availability scores is also revealed. Finally, we are buying substances by looking at the molecular graphs or molecular formulas. Thus, those molecules that have a higher number of atoms look more attractive and are, on average, also more expensive. Our study shows how data binning could be used as an informative method when analyzing big data in chemistry.

  9. Molecular descriptor data explain market prices of a large commercial chemical compound library.

    PubMed

    Polanski, Jaroslaw; Kucia, Urszula; Duszkiewicz, Roksana; Kurczyk, Agata; Magdziarz, Tomasz; Gasteiger, Johann

    2016-06-23

    The relationship between the structure and a property of a chemical compound is an essential concept in chemistry guiding, for example, drug design. Actually, however, we need economic considerations to fully understand the fate of drugs on the market. We are performing here for the first time the exploration of quantitative structure-economy relationships (QSER) for a large dataset of a commercial building block library of over 2.2 million chemicals. This investigation provided molecular statistics that shows that on average what we are paying for is the quantity of matter. On the other side, the influence of synthetic availability scores is also revealed. Finally, we are buying substances by looking at the molecular graphs or molecular formulas. Thus, those molecules that have a higher number of atoms look more attractive and are, on average, also more expensive. Our study shows how data binning could be used as an informative method when analyzing big data in chemistry.

  10. Molecular descriptor data explain market prices of a large commercial chemical compound library

    PubMed Central

    Polanski, Jaroslaw; Kucia, Urszula; Duszkiewicz, Roksana; Kurczyk, Agata; Magdziarz, Tomasz; Gasteiger, Johann

    2016-01-01

    The relationship between the structure and a property of a chemical compound is an essential concept in chemistry guiding, for example, drug design. Actually, however, we need economic considerations to fully understand the fate of drugs on the market. We are performing here for the first time the exploration of quantitative structure-economy relationships (QSER) for a large dataset of a commercial building block library of over 2.2 million chemicals. This investigation provided molecular statistics that shows that on average what we are paying for is the quantity of matter. On the other side, the influence of synthetic availability scores is also revealed. Finally, we are buying substances by looking at the molecular graphs or molecular formulas. Thus, those molecules that have a higher number of atoms look more attractive and are, on average, also more expensive. Our study shows how data binning could be used as an informative method when analyzing big data in chemistry. PMID:27334348

  11. Panel docking of small-molecule libraries - Prospects to improve efficiency of lead compound discovery.

    PubMed

    Sarnpitak, Pakornwit; Mujumdar, Prashant; Taylor, Paul; Cross, Megan; Coster, Mark J; Gorse, Alain-Dominique; Krasavin, Mikhail; Hofmann, Andreas

    2015-11-01

    Computational docking as a means to prioritise small molecules in drug discovery projects remains a highly popular in silico screening approach. Contemporary docking approaches without experimental parametrisation can reliably differentiate active and inactive chemotypes in a protein binding site, but the absence of a correlation between the score of a predicted binding pose and the biological activity of the molecule presents a clear limitation. Several novel or improved computational approaches have been developed in the recent past to aid in screening and profiling of small-molecule ligands for drug discovery, but also more broadly in developing conceptual relationships between different protein targets by chemical probing. Among those new methodologies is a strategy known as inverse virtual screening, which involves the docking of a compound into different protein structures. In the present article, we review the different computational screening methodologies that employ docking of atomic models, and, by means of a case study, present an approach that expands the inverse virtual screening concept. By computationally screening a reasonably sized library of 1235 compounds against a panel of 48 mostly human kinases, we have been able to identify five groups of putative lead compounds with substantial diversity when compared to each other. One representative of each of the five groups was synthesised, and tested in kinase inhibition assays, yielding two compounds with micro-molar inhibition in five human kinases. This highly economic and cost-effective methodology holds great promise for drug discovery projects, especially in cases where a group of target proteins share high structural similarity in their binding sites.

  12. Measurement of volatile organic compounds (VOCs) in libraries and archives in Florence (Italy).

    PubMed

    Cincinelli, A; Martellini, T; Amore, A; Dei, L; Marrazza, G; Carretti, E; Belosi, F; Ravegnani, F; Leva, P

    2016-12-01

    Indoor air samples from libraries and archives in Florence, Italy, were collected and analysed for a variety of volatile organic compounds. The aim was to perform a characterisation of the indoor air quality, and try to elucidate if there are VOCs that may cause or result from the determination of the cultural heritage institutions. All compounds of interest were regularly detected, with BTEXs (Benzene, Toluene, Ethylbenzene, Xylenes) being the most abundant and followed by cyclic volatile methylsiloxanes, aldehydes, terpenes and organic acids. The prevalence and qualitative characteristics, such as concentrations, profiles and indoor/outdoor ratios of BTEXs underline the important influence of the outdoor air infiltrations on the indoor air concentrations. Acetic acid that is a substance that can oxidise books and other exposed objects was detected at concentrations ranging between 1.04 and 18.9μgm(-3), while furfural, that is a known marker of paper degradation, was constantly present at concentrations that ranged between 5.26 and 32.6μgm(-3). This work shows the importance that indoor air quality monitoring campaigns can have in order to give early warning to cultural heritage institution managers about the impact that indoor air quality can have on exposed and/or preserved objects.

  13. Optimization of the Magnetic Recovery of Hits from One-Bead-One-Compound Library Screens.

    PubMed

    Mendes, Kimberly; Ndungu, J M; Clark, Lorraine F; Kodadek, Thomas

    2015-09-14

    On-bead screening of one-bead-one-compound (OBOC) libraries is a useful procedure for the identification of protein ligands. An important aspect of this experiment is the method by which beads that bind the target protein are separated from those that do not. Ideally, such a method would be rapid and convenient and result in the isolation of 100% of the "hits" with no false positives (beads that display compounds that are not good ligands for the target). We introduced a technique in which beads that have bound a labeled target protein can be magnetized, thus allowing their convenient isolation ( Astle et al. Chem. Biol. 2010 , 17 , 38 - 45 ). However, recent work in our laboratory and others has shown that magnetic hit recovery can result in the isolation of large numbers of false positives and has also suggested that many true hit beads are missed. In this study, we employ a well-defined model system to examine the efficiency of various magnetic hit isolation protocols. We show that the choice of reagents and the particular operations employed are critical for optimal results.

  14. Development and experimental test of support vector machines virtual screening method for searching Src inhibitors from large compound libraries

    PubMed Central

    2012-01-01

    Background Src plays various roles in tumour progression, invasion, metastasis, angiogenesis and survival. It is one of the multiple targets of multi-target kinase inhibitors in clinical uses and trials for the treatment of leukemia and other cancers. These successes and appearances of drug resistance in some patients have raised significant interest and efforts in discovering new Src inhibitors. Various in-silico methods have been used in some of these efforts. It is desirable to explore additional in-silico methods, particularly those capable of searching large compound libraries at high yields and reduced false-hit rates. Results We evaluated support vector machines (SVM) as virtual screening tools for searching Src inhibitors from large compound libraries. SVM trained and tested by 1,703 inhibitors and 63,318 putative non-inhibitors correctly identified 93.53%~ 95.01% inhibitors and 99.81%~ 99.90% non-inhibitors in 5-fold cross validation studies. SVM trained by 1,703 inhibitors reported before 2011 and 63,318 putative non-inhibitors correctly identified 70.45% of the 44 inhibitors reported since 2011, and predicted as inhibitors 44,843 (0.33%) of 13.56M PubChem, 1,496 (0.89%) of 168 K MDDR, and 719 (7.73%) of 9,305 MDDR compounds similar to the known inhibitors. Conclusions SVM showed comparable yield and reduced false hit rates in searching large compound libraries compared to the similarity-based and other machine-learning VS methods developed from the same set of training compounds and molecular descriptors. We tested three virtual hits of the same novel scaffold from in-house chemical libraries not reported as Src inhibitor, one of which showed moderate activity. SVM may be potentially explored for searching Src inhibitors from large compound libraries at low false-hit rates. PMID:23173901

  15. Rapid access to compound libraries through flow technology: fully automated synthesis of a 3-aminoindolizine library via orthogonal diversification.

    PubMed

    Lange, Paul P; James, Keith

    2012-10-08

    A novel methodology for the synthesis of druglike heterocycle libraries has been developed through the use of flow reactor technology. The strategy employs orthogonal modification of a heterocyclic core, which is generated in situ, and was used to construct both a 25-membered library of druglike 3-aminoindolizines, and selected examples of a 100-member virtual library. This general protocol allows a broad range of acylation, alkylation and sulfonamidation reactions to be performed in conjunction with a tandem Sonogashira coupling/cycloisomerization sequence. All three synthetic steps were conducted under full automation in the flow reactor, with no handling or isolation of intermediates, to afford the desired products in good yields. This fully automated, multistep flow approach opens the way to highly efficient generation of druglike heterocyclic systems as part of a lead discovery strategy or within a lead optimization program.

  16. Design of a Microfluidic Chip for Magnetic-Activated Sorting of One-Bead-One-Compound Libraries.

    PubMed

    Cho, Choi-Fong; Lee, Kyungheon; Speranza, Maria-Carmela; Bononi, Fernanda C; Viapiano, Mariano S; Luyt, Leonard G; Weissleder, Ralph; Chiocca, E Antonio; Lee, Hakho; Lawler, Sean E

    2016-06-13

    Molecular targeting using ligands specific to disease markers has shown great promise for early detection and directed therapy. Bead-based combinatorial libraries have served as powerful tools for the discovery of novel targeting agents. Screening platforms employing magnetic capture have been used to achieve rapid and efficient identification of high-affinity ligands from one-bead-one-compound (OBOC) libraries. Traditional manual methodologies to isolate magnetized "hit" beads are tedious and lack accuracy, and existing instruments to expedite bead sorting tend to be costly and complex. Here, we describe the design and construction of a simple and inexpensive microfluidic magnetic sorting device using standard photolithography and soft lithography approaches to facilitate high-throughput isolation of magnetized positive hit beads from combinatorial libraries. We have demonstrated that the device is able to sort magnetized beads with superior accuracy compared to conventional manual sorting approaches. This chip offers a very convenient yet inexpensive alternative for screening OBOC libraries.

  17. Creating the New from the Old: Combinatorial Libraries Generation with Machine-Learning-Based Compound Structure Optimization.

    PubMed

    Podlewska, Sabina; Czarnecki, Wojciech M; Kafel, Rafał; Bojarski, Andrzej J

    2017-02-27

    The growing computational abilities of various tools that are applied in the broadly understood field of computer-aided drug design have led to the extreme popularity of virtual screening in the search for new biologically active compounds. Most often, the source of such molecules consists of commercially available compound databases, but they can also be searched for within the libraries of structures generated in silico from existing ligands. Various computational combinatorial approaches are based solely on the chemical structure of compounds, using different types of substitutions for new molecules formation. In this study, the starting point for combinatorial library generation was the fingerprint referring to the optimal substructural composition in terms of the activity toward a considered target, which was obtained using a machine learning-based optimization procedure. The systematic enumeration of all possible connections between preferred substructures resulted in the formation of target-focused libraries of new potential ligands. The compounds were initially assessed by machine learning methods using a hashed fingerprint to represent molecules; the distribution of their physicochemical properties was also investigated, as well as their synthetic accessibility. The examination of various fingerprints and machine learning algorithms indicated that the Klekota-Roth fingerprint and support vector machine were an optimal combination for such experiments. This study was performed for 8 protein targets, and the obtained compound sets and their characterization are publically available at http://skandal.if-pan.krakow.pl/comb_lib/ .

  18. Studying a Drug-like, RNA-Focused Small Molecule Library Identifies Compounds That Inhibit RNA Toxicity in Myotonic Dystrophy

    PubMed Central

    Rzuczek, Suzanne G.; Southern, Mark R.; Disney, Matthew D.

    2016-01-01

    There are many RNA targets in the transcriptome to which small molecule chemical probes and lead therapeutics are desired. However, identifying compounds that bind and modulate RNA function in cellulo is difficult. Although rational design approaches have been developed, they are still in their infancies and leave many RNAs “undruggable”. In an effort to develop a small molecule library that is biased for binding RNA, we computationally identified “drug-like” compounds from screening collections that have favorable properties for binding RNA and for suitability as lead drugs. As proof-of-concept, this collection was screened for binding to and modulating the cellular dysfunction of the expanded repeating RNA (r(CUG)exp) that causes myotonic dystrophy type 1. Hit compounds bind the target in cellulo, as determined by the target identification approach Competitive Chemical Cross-Linking and Isolation by Pull-down (C-ChemCLIP), and selectively improve several disease-associated defects. The best compounds identified from our 320-member library are more potent in cellulo than compounds identified by high-throughput screening (HTS) campaigns against this RNA. Furthermore, the compound collection has a higher hit rate (9% compared to 0.01–3%), and the bioactive compounds identified are not charged; thus, RNA can be “drugged” with compounds that have favorable pharmacological properties. Finally, this RNA-focused small molecule library may serve as a useful starting point to identify lead “drug-like” chemical probes that affect the biological (dys)function of other RNA targets by direct target engagement. PMID:26414664

  19. Studying a Drug-like, RNA-Focused Small Molecule Library Identifies Compounds That Inhibit RNA Toxicity in Myotonic Dystrophy.

    PubMed

    Rzuczek, Suzanne G; Southern, Mark R; Disney, Matthew D

    2015-12-18

    There are many RNA targets in the transcriptome to which small molecule chemical probes and lead therapeutics are desired. However, identifying compounds that bind and modulate RNA function in cellulo is difficult. Although rational design approaches have been developed, they are still in their infancies and leave many RNAs "undruggable". In an effort to develop a small molecule library that is biased for binding RNA, we computationally identified "drug-like" compounds from screening collections that have favorable properties for binding RNA and for suitability as lead drugs. As proof-of-concept, this collection was screened for binding to and modulating the cellular dysfunction of the expanded repeating RNA (r(CUG)(exp)) that causes myotonic dystrophy type 1. Hit compounds bind the target in cellulo, as determined by the target identification approach Competitive Chemical Cross-Linking and Isolation by Pull-down (C-ChemCLIP), and selectively improve several disease-associated defects. The best compounds identified from our 320-member library are more potent in cellulo than compounds identified by high-throughput screening (HTS) campaigns against this RNA. Furthermore, the compound collection has a higher hit rate (9% compared to 0.01-3%), and the bioactive compounds identified are not charged; thus, RNA can be "drugged" with compounds that have favorable pharmacological properties. Finally, this RNA-focused small molecule library may serve as a useful starting point to identify lead "drug-like" chemical probes that affect the biological (dys)function of other RNA targets by direct target engagement.

  20. Bis-Acridines as Lead Antiparasitic Agents: Structure-Activity Analysis of a Discrete Compound Library In Vitro▿

    PubMed Central

    Caffrey, Conor R.; Steverding, Dietmar; Swenerton, Ryan K.; Kelly, Ben; Walshe, Deirdre; Debnath, Anjan; Zhou, Yuan-Min; Doyle, Patricia S.; Fafarman, Aaron T.; Zorn, Julie A.; Land, Kirkwood M.; Beauchene, Jessica; Schreiber, Kimberly; Moll, Heidrun; Ponte-Sucre, Alicia; Schirmeister, Tanja; Saravanamuthu, Ahilan; Fairlamb, Alan H.; Cohen, Fred E.; McKerrow, James H.; Weisman, Jennifer L.; May, Barnaby C. H.

    2007-01-01

    Parasitic diseases are of enormous public health significance in developing countries—a situation compounded by the toxicity of and resistance to many current chemotherapeutics. We investigated a focused library of 18 structurally diverse bis-acridine compounds for in vitro bioactivity against seven protozoan and one helminth parasite species and compared the bioactivities and the cytotoxicities of these compounds toward various mammalian cell lines. Structure-activity relationships demonstrated the influence of both the bis-acridine linker structure and the terminal acridine heterocycle on potency and cytotoxicity. The bioactivity of polyamine-linked acridines required a minimum linker length of approximately 10 Å. Increasing linker length resulted in bioactivity against most parasites but also cytotoxicity toward mammalian cells. N alkylation, but less so N acylation, of the polyamine linker ameliorated cytotoxicity while retaining bioactivity with 50% effective concentration (EC50) values similar to or better than those measured for standard drugs. Substitution of the polyamine for either an alkyl or a polyether linker maintained bioactivity and further alleviated cytotoxicity. Polyamine-linked compounds in which the terminal acridine heterocycle had been replaced with an aza-acridine also maintained acceptable therapeutic indices. The most potent compounds recorded low- to mid-nanomolar EC50 values against Plasmodium falciparum and Trypanosoma brucei; otherwise, low-micromolar potencies were measured. Importantly, the bioactivity of the library was independent of P. falciparum resistance to chloroquine. Compound bioactivity was a function of neither the potential to bis-intercalate DNA nor the inhibition of trypanothione reductase, an important drug target in trypanosomatid parasites. Our approach illustrates the usefulness of screening focused compound libraries against multiple parasite targets. Some of the bis-acridines identified here may represent

  1. Stochastic voyages into uncharted chemical space produce a representative library of all possible drug-like compounds.

    PubMed

    Virshup, Aaron M; Contreras-García, Julia; Wipf, Peter; Yang, Weitao; Beratan, David N

    2013-05-15

    The "small molecule universe" (SMU), the set of all synthetically feasible organic molecules of 500 Da molecular weight or less, is estimated to contain over 10(60) structures, making exhaustive searches for structures of interest impractical. Here, we describe the construction of a "representative universal library" spanning the SMU that samples the full extent of feasible small molecule chemistries. This library was generated using the newly developed Algorithm for Chemical Space Exploration with Stochastic Search (ACSESS). ACSESS makes two important contributions to chemical space exploration: it allows the systematic search of the unexplored regions of the small molecule universe, and it facilitates the mining of chemical libraries that do not yet exist, providing a near-infinite source of diverse novel compounds.

  2. Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet-Spengler cyclization/metal-catalyzed cross coupling/amidation sequence.

    PubMed

    Petersen, Rico; Cohrt, A Emil; Petersen, Michael Åxman; Wu, Peng; Clausen, Mads H; Nielsen, Thomas E

    2015-06-01

    Molecular libraries of natural product-like and structurally diverse compounds are attractive in early drug discovery campaigns. In here, we present synthetic methodology for library production of hexahydropyrrolo[2,1-a]isoquinoline (HPIQ) compounds. Two advanced HPIQ intermediates, both incorporating two handles for diversification, were synthesized through an oxidative cleavage/Pictet-Spengler reaction sequence in high overall yields. A subsequent metal-catalyzed cross coupling/amidation protocol was developed and its utility in library synthesis was validated by construction of a 20-membered natural product-like molecular library in good overall yields.

  3. From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries.

    PubMed

    Breinbauer, Rolf; Vetter, Ingrid R; Waldmann, Herbert

    2002-08-16

    In the continuing effort to find small molecules that alter protein function and ultimately might lead to new drugs, combinatorial chemistry has emerged as a very powerful tool. Contrary to original expectations that large libraries would result in the discovery of many hit and lead structures, it has been recognized that the biological relevance, design, and diversity of the library are more important. As the universe of conceivable compounds is almost infinite, the question arises: where is a biologically validated starting point from which to build a combinatorial library? Nature itself might provide an answer: natural products have been evolved to bind to proteins. Recent results in structural biology and bioinformatics indicate that the number of distinct protein families and folds is fairly limited. Often the same structural domain is used by many proteins in a more or less modified form created by divergent evolution. Recent progress in solid-phase organic synthesis has enabled the synthesis of combinatorial libraries based on the structure of complex natural products. It can be envisioned that natural-product-based combinatorial synthesis may permit hit or lead compounds to be found with enhanced probability and quality.

  4. PGVL Hub: An integrated desktop tool for medicinal chemists to streamline design and synthesis of chemical libraries and singleton compounds.

    PubMed

    Peng, Zhengwei; Yang, Bo; Mattaparti, Sarathy; Shulok, Thom; Thacher, Thomas; Kong, James; Kostrowicki, Jaroslav; Hu, Qiyue; Na, James; Zhou, Joe Zhongxiang; Klatte, David; Chao, Bo; Ito, Shogo; Clark, John; Sciammetta, Nunzio; Coner, Bob; Waller, Chris; Kuki, Atsuo

    2011-01-01

    PGVL Hub is an integrated molecular design desktop tool that has been developed and globally deployed throughout Pfizer discovery research units to streamline the design and synthesis of combinatorial libraries and singleton compounds. This tool supports various workflows for design of singletons, combinatorial libraries, and Markush exemplification. It also leverages the proprietary PGVL virtual space (which contains 10(14) molecules spanned by experimentally derived synthesis protocols and suitable reactants) for lead idea generation, lead hopping, and library design. There had been an intense focus on ease of use, good performance and robustness, and synergy with existing desktop tools such as ISIS/Draw and SpotFire. In this chapter we describe the three-tier enterprise software architecture, key data structures that enable a wide variety of design scenarios and workflows, major technical challenges encountered and solved, and lessons learned during its development and deployment throughout its production cycles. In addition, PGVL Hub represents an extendable and enabling platform to support future innovations in library and singleton compound design while being a proven channel to deliver those innovations to medicinal chemists on a global scale.

  5. Discovery of inhibitors of Shiga toxin type 2 by on-plate generation and screening of a focused compound library.

    PubMed

    Dasgupta, Somnath; Kitov, Pavel I; Sadowska, Joanna M; Bundle, David R

    2014-02-03

    A new microtiter-plate-based method for the rapid generation and evaluation of focused compound libraries was developed and applied to screening ligand analogues for the E. coli Shiga-like toxin Stx2a. The method is general, it mitigates the masking of intrinsic affinity gains by multivalency and enables the discovery of potential hits when starting from ligands that exhibit extremely low affinity with proteins that depend on multivalency for their function.

  6. Screening a Small Library of Xanthones for Antitumor Activity and Identification of a Hit Compound which Induces Apoptosis.

    PubMed

    Barbosa, João; Lima, Raquel T; Sousa, Diana; Gomes, Ana Sara; Palmeira, Andreia; Seca, Hugo; Choosang, Kantima; Pakkong, Pannee; Bousbaa, Hassan; Pinto, Madalena M; Sousa, Emília; Vasconcelos, M Helena; Pedro, Madalena

    2016-01-13

    Our previous work has described a library of thioxanthones designed to have dual activity as P-glycoprotein modulators and antitumor agents. Some of these compounds had shown a significant cell growth inhibitory activity towards leukemia cell lines, without affecting the growth of non-tumor human fibroblasts. However, their effect in cell lines derived from solid tumors has not been previously studied. The present work aimed at: (i) screening this small series of compounds from an in-house library, for their in vitro cell growth inhibitory activity in human tumor cell lines derived from solid tumors; and (ii) initiate a study of the effect of the most potent compound on apoptosis. The tumor cell growth inhibitory effect of 27 compounds was first analysed in different human tumor cell lines, allowing the identification of a hit compound, TXA1. Its hydrochloride salt TXA1·HCl was then synthesized, to improve solubility and bioavailability. Both TXA1 and TXA1·HCl inhibited the growth of MCF-7, NCI-H460, A375-C5, HeLa, 786-O, Caki-2 and AGS cell lines. The effect of TXA1·HCl in MCF-7 cells was found to be irreversible and was associated, at least in part, with an increase in cellular apoptosis.

  7. Synthesis and Evaluation of a Library of Trifunctional Scaffold-Derived Compounds as Modulators of the Insulin Receptor.

    PubMed

    Fabre, Benjamin; Pícha, Jan; Vaněk, Václav; Selicharová, Irena; Chrudinová, Martina; Collinsová, Michaela; Žáková, Lenka; Buděšínský, Miloš; Jiráček, Jiří

    2016-12-12

    We designed a combinatorial library of trifunctional scaffold-derived compounds, which were derivatized with 30 different in-house-made azides. The compounds were proposed to mimic insulin receptor (IR)-binding epitopes in the insulin molecule and bind to and activate this receptor. This work has enabled us to test our synthetic and biological methodology and to prove its robustness and reliability for the solid-phase synthesis and testing of combinatorial libraries of the trifunctional scaffold-derived compounds. Our effort resulted in the discovery of two compounds, which were able to weakly induce the autophosphorylation of IR and weakly bind to this receptor at a 0.1 mM concentration. Despite these modest biological results, which well document the well-known difficulty in modulating protein-protein interactions, this study represents a unique example of targeting the IR with a set of nonpeptide compounds that were specifically designed and synthesized for this purpose. We believe that this work can open new perspectives for the development of next-generation insulin mimetics based on the scaffold structure.

  8. High content screening of a kinase-focused library reveals compounds broadly-active against dengue viruses.

    PubMed

    Cruz, Deu John M; Koishi, Andrea Cristine; Taniguchi, Juliana Bosso; Li, Xiaolan; Milan Bonotto, Rafaela; No, Joo Hwan; Kim, Keum Hyun; Baek, Sungmin; Kim, Hee Young; Windisch, Marc Peter; Pamplona Mosimann, Ana Luiza; de Borba, Luana; Liuzzi, Michel; Hansen, Michael Adsetts Edberg; Duarte dos Santos, Claudia Nunes; Freitas-Junior, Lucio Holanda

    2013-01-01

    Dengue virus is a mosquito-borne flavivirus that has a large impact in global health. It is considered as one of the medically important arboviruses, and developing a preventive or therapeutic solution remains a top priority in the medical and scientific community. Drug discovery programs for potential dengue antivirals have increased dramatically over the last decade, largely in part to the introduction of high-throughput assays. In this study, we have developed an image-based dengue high-throughput/high-content assay (HT/HCA) using an innovative computer vision approach to screen a kinase-focused library for anti-dengue compounds. Using this dengue HT/HCA, we identified a group of compounds with a 4-(1-aminoethyl)-N-methylthiazol-2-amine as a common core structure that inhibits dengue viral infection in a human liver-derived cell line (Huh-7.5 cells). Compounds CND1201, CND1203 and CND1243 exhibited strong antiviral activities against all four dengue serotypes. Plaque reduction and time-of-addition assays suggests that these compounds interfere with the late stage of viral infection cycle. These findings demonstrate that our image-based dengue HT/HCA is a reliable tool that can be used to screen various chemical libraries for potential dengue antiviral candidates.

  9. Measurement of volatile organic compounds emitted in libraries and archives: an inferential indicator of paper decay?

    PubMed Central

    2012-01-01

    Background A sampling campaign of indoor air was conducted to assess the typical concentration of indoor air pollutants in 8 National Libraries and Archives across the U.K. and Ireland. At each site, two locations were chosen that contained various objects in the collection (paper, parchment, microfilm, photographic material etc.) and one location was chosen to act as a sampling reference location (placed in a corridor or entrance hallway). Results Of the locations surveyed, no measurable levels of sulfur dioxide were detected and low formaldehyde vapour (< 18 μg m-3) was measured throughout. Acetic and formic acids were measured in all locations with, for the most part, higher acetic acid levels in areas with objects compared to reference locations. A large variety of volatile organic compounds (VOCs) was measured in all locations, in variable concentrations, however furfural was the only VOC to be identified consistently at higher concentration in locations with paper-based collections, compared to those locations without objects. To cross-reference the sampling data with VOCs emitted directly from books, further studies were conducted to assess emissions from paper using solid phase microextraction (SPME) fibres and a newly developed method of analysis; collection of VOCs onto a polydimethylsiloxane (PDMS) elastomer strip. Conclusions In this study acetic acid and furfural levels were consistently higher in concentration when measured in locations which contained paper-based items. It is therefore suggested that both acetic acid and furfural (possibly also trimethylbenzenes, ethyltoluene, decane and camphor) may be present in the indoor atmosphere as a result of cellulose degradation and together may act as an inferential non-invasive marker for the deterioration of paper. Direct VOC sampling was successfully achieved using SPME fibres and analytes found in the indoor air were also identified as emissive by-products from paper. Finally a new non

  10. Novel Anti-Campylobacter Compounds Identified Using High Throughput Screening of a Pre-selected Enriched Small Molecules Library

    PubMed Central

    Kumar, Anand; Drozd, Mary; Pina-Mimbela, Ruby; Xu, Xiulan; Helmy, Yosra A.; Antwi, Janet; Fuchs, James R.; Nislow, Corey; Templeton, Jillian; Blackall, Patrick J.; Rajashekara, Gireesh

    2016-01-01

    Campylobacter is a leading cause of foodborne bacterial gastroenteritis worldwide and infections can be fatal. The emergence of antibiotic-resistant Campylobacter spp. necessitates the development of new antimicrobials. We identified novel anti-Campylobacter small molecule inhibitors using a high throughput growth inhibition assay. To expedite screening, we made use of a “bioactive” library of 4182 compounds that we have previously shown to be active against diverse microbes. Screening for growth inhibition of Campylobacter jejuni, identified 781 compounds that were either bactericidal or bacteriostatic at a concentration of 200 μM. Seventy nine of the bactericidal compounds were prioritized for secondary screening based on their physico-chemical properties. Based on the minimum inhibitory concentration against a diverse range of C. jejuni and a lack of effect on gut microbes, we selected 12 compounds. No resistance was observed to any of these 12 lead compounds when C. jejuni was cultured with lethal or sub-lethal concentrations suggesting that C. jejuni is less likely to develop resistance to these compounds. Top 12 compounds also possessed low cytotoxicity to human intestinal epithelial cells (Caco-2 cells) and no hemolytic activity against sheep red blood cells. Next, these 12 compounds were evaluated for ability to clear C. jejuni in vitro. A total of 10 compounds had an anti-C. jejuni effect in Caco-2 cells with some effective even at 25 μM concentrations. These novel 12 compounds belong to five established antimicrobial chemical classes; piperazines, aryl amines, piperidines, sulfonamide, and pyridazinone. Exploitation of analogs of these chemical classes may provide Campylobacter specific drugs that can be applied in both human and animal medicine. PMID:27092106

  11. Novel Anti-Campylobacter Compounds Identified Using High Throughput Screening of a Pre-selected Enriched Small Molecules Library.

    PubMed

    Kumar, Anand; Drozd, Mary; Pina-Mimbela, Ruby; Xu, Xiulan; Helmy, Yosra A; Antwi, Janet; Fuchs, James R; Nislow, Corey; Templeton, Jillian; Blackall, Patrick J; Rajashekara, Gireesh

    2016-01-01

    Campylobacter is a leading cause of foodborne bacterial gastroenteritis worldwide and infections can be fatal. The emergence of antibiotic-resistant Campylobacter spp. necessitates the development of new antimicrobials. We identified novel anti-Campylobacter small molecule inhibitors using a high throughput growth inhibition assay. To expedite screening, we made use of a "bioactive" library of 4182 compounds that we have previously shown to be active against diverse microbes. Screening for growth inhibition of Campylobacter jejuni, identified 781 compounds that were either bactericidal or bacteriostatic at a concentration of 200 μM. Seventy nine of the bactericidal compounds were prioritized for secondary screening based on their physico-chemical properties. Based on the minimum inhibitory concentration against a diverse range of C. jejuni and a lack of effect on gut microbes, we selected 12 compounds. No resistance was observed to any of these 12 lead compounds when C. jejuni was cultured with lethal or sub-lethal concentrations suggesting that C. jejuni is less likely to develop resistance to these compounds. Top 12 compounds also possessed low cytotoxicity to human intestinal epithelial cells (Caco-2 cells) and no hemolytic activity against sheep red blood cells. Next, these 12 compounds were evaluated for ability to clear C. jejuni in vitro. A total of 10 compounds had an anti-C. jejuni effect in Caco-2 cells with some effective even at 25 μM concentrations. These novel 12 compounds belong to five established antimicrobial chemical classes; piperazines, aryl amines, piperidines, sulfonamide, and pyridazinone. Exploitation of analogs of these chemical classes may provide Campylobacter specific drugs that can be applied in both human and animal medicine.

  12. Screening and identification of mimotopes of the major shrimp allergen tropomyosin using one-bead-one-compound peptide libraries

    PubMed Central

    Leung, Nicki YH; Wai, Christine YY; Ho, Marco HK; Liu, Ruiwu; Lam, Kit S; Wang, Jin Jun; Shu, Shang An; Chu, Ka Hou; Leung, Patrick SC

    2017-01-01

    The one-bead-one-compound (OBOC) combinatorial peptide library is a powerful tool to identify ligand and receptor interactions. Here, we applied the OBOC library technology to identify mimotopes specific to the immunoglobulin E (IgE) epitopes of the major shellfish allergen tropomyosin. OBOC peptide libraries with 8–12 amino acid residues were screened with serum samples from patients with shellfish allergy for IgE mimotopes of tropomyosin. Twenty-five mimotopes were identified from the screening and their binding reactivity to tropomyosin-specific IgE was confirmed by peptide ELISA. These mimotopes could be divided into seven clusters based on sequence homology, and epitope mapping by EpiSearch of the clustered mimotopes was performed to characterize and confirm the validity of mimotopes. Five out of six of the predicted epitopes were found to overlap with previously identified epitopes of tropomyosin. To further confirm the mimicry potential of mimotopes, BALB/c mice were immunized with mimotopes conjugated to keyhole limpet hemocyanin and assayed for their capacity to induce tropomyosin-specific antibodies. BALB/c mice that received mimotope immunization were found to have an elevated level of tropomyosin-specific immunoglobulin G, but not mice that received an irrelevant mimotope. This study pioneers the successful application of the OBOC libraries using whole sera to screen and identify multiple shrimp allergen mimotopes and validates their mimicry potential using in vitro, in vivo, and in silico methods. PMID:26364917

  13. Annotated compound data for modulators of detergent-solubilised or lipid-reconstituted respiratory type II NADH dehydrogenase activity obtained by compound library screening

    PubMed Central

    Dunn, Elyse A.; Cook, Gregory M.; Heikal, Adam

    2015-01-01

    The energy-generating membrane protein NADH dehydrogenase (NDH-2), a proposed antibacterial drug target (see “Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs” Weinstein et al. 2005 [1]), was screened for modulators of activity in either detergent-solublised or lipid reconstituted (proteolipsome) form. Here we present an annotated list of compounds identified in a small-scale screen against NDH-2. The dataset contains information regarding the libraries screened, the identities of hit compounds and the physicochemical properties governing solubility and permeability. The implications of these data for future antibiotic discovery are discussed in our associated report, “Comparison of lipid and detergent enzyme environments for identifying inhibitors of membrane-bound energy-transducing proteins” [2]. PMID:26862571

  14. Annotated compound data for modulators of detergent-solubilised or lipid-reconstituted respiratory type II NADH dehydrogenase activity obtained by compound library screening.

    PubMed

    Dunn, Elyse A; Cook, Gregory M; Heikal, Adam

    2016-03-01

    The energy-generating membrane protein NADH dehydrogenase (NDH-2), a proposed antibacterial drug target (see "Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs" Weinstein et al. 2005 [1]), was screened for modulators of activity in either detergent-solublised or lipid reconstituted (proteolipsome) form. Here we present an annotated list of compounds identified in a small-scale screen against NDH-2. The dataset contains information regarding the libraries screened, the identities of hit compounds and the physicochemical properties governing solubility and permeability. The implications of these data for future antibiotic discovery are discussed in our associated report, "Comparison of lipid and detergent enzyme environments for identifying inhibitors of membrane-bound energy-transducing proteins" [2].

  15. Stochastic voyages into uncharted chemical space produce a representative library of all possible drug-like compounds

    PubMed Central

    Virshup, Aaron M.; Contreras-García, Julia; Wipf, Peter; Yang, Weitao; Beratan, David N.

    2013-01-01

    The “small molecule universe” (SMU), the set of all synthetically feasible organic molecules of 500 Daltons molecular weight or less, is estimated to contain over 1060 structures, making exhaustive searches for structures of interest impractical. Here, we describe the construction of a “representative universal library” spanning the SMU that samples the full extent of feasible small molecule chemistries. This library was generated using the newly developed Algorithm for Chemical Space Exploration with Stochastic Search (ACSESS). ACSESS makes two important contributions to chemical space exploration: it allows the systematic search of the unexplored regions of the small molecule universe, and it facilitates the mining of chemical libraries that do not yet exist, providing a near-infinite source of diverse novel compounds. PMID:23548177

  16. Identification of B. anthracis N(5)-carboxyaminoimidazole ribonucleotide mutase (PurE) active site binding compounds via fragment library screening.

    PubMed

    Lei, Hao; Jones, Christopher; Zhu, Tian; Patel, Kavankumar; Wolf, Nina M; Fung, Leslie W-M; Lee, Hyun; Johnson, Michael E

    2016-02-15

    The de novo purine biosynthesis pathway is an attractive target for antibacterial drug design, and PurE from this pathway has been identified to be crucial for Bacillus anthracis survival in serum. In this study we adopted a fragment-based hit discovery approach, using three screening methods-saturation transfer difference nucleus magnetic resonance (STD-NMR), water-ligand observed via gradient spectroscopy (WaterLOGSY) NMR, and surface plasmon resonance (SPR), against B. anthracis PurE (BaPurE) to identify active site binding fragments by initially testing 352 compounds in a Zenobia fragment library. Competition STD NMR with the BaPurE product effectively eliminated non-active site binding hits from the primary hits, selecting active site binders only. Binding affinities (dissociation constant, KD) of these compounds varied between 234 and 301μM. Based on test results from the Zenobia compounds, we subsequently developed and applied a streamlined fragment screening strategy to screen a much larger library consisting of 3000 computationally pre-selected fragments. Thirteen final fragment hits were confirmed to exhibit binding affinities varying from 14μM to 700μM, which were categorized into five different basic scaffolds. All thirteen fragment hits have ligand efficiencies higher than 0.30. We demonstrated that at least two fragments from two different scaffolds exhibit inhibitory activity against the BaPurE enzyme.

  17. Identification of Three Classes of Heteroaromatic Compounds with Activity against Intracellular Trypanosoma cruzi by Chemical Library Screening

    PubMed Central

    Bettiol, Esther; Samanovic, Marie; Murkin, Andrew S.; Raper, Jayne; Buckner, Frederick; Rodriguez, Ana

    2009-01-01

    The development of new drugs against Chagas disease is a priority since the currently available medicines have toxic effects, partial efficacy and are targeted against the acute phase of disease. At present, there is no drug to treat the chronic stage. In this study, we have optimized a whole cell-based assay for high throughput screening of compounds that inhibit infection of mammalian cells by Trypanosoma cruzi trypomastigotes. A 2000-compound chemical library was screened using a recombinant T. cruzi (Tulahuen strain) expressing β-galactosidase. Three hits were selected for their high activity against T. cruzi and low toxicity to host cells in vitro: PCH1, NT1 and CX1 (IC50: 54, 190 and 23 nM, respectively). Each of these three compounds presents a different mechanism of action on intracellular proliferation of T. cruzi amastigotes. CX1 shows strong trypanocidal activity, an essential characteristic for the development of drugs against the chronic stage of Chagas disease where parasites are found intracellular in a quiescent stage. NT1 has a trypanostatic effect, while PCH1 affects parasite division. The three compounds also show high activity against intracellular T. cruzi from the Y strain and against the related kinetoplastid species Leishmania major and L. amazonensis. Characterization of the anti–T. cruzi activity of molecules chemically related to the three library hits allowed the selection of two compounds with IC50 values of 2 nM (PCH6 and CX2). These values are approximately 100 times lower than those of the medicines used in patients against T. cruzi. These results provide new candidate molecules for the development of treatments against Chagas disease and leishmaniasis. PMID:19238193

  18. Effect of training data size and noise level on support vector machines virtual screening of genotoxic compounds from large compound libraries

    NASA Astrophysics Data System (ADS)

    Kumar, Pankaj; Ma, Xiaohua; Liu, Xianghui; Jia, Jia; Bucong, Han; Xue, Ying; Li, Ze Rong; Yang, Sheng Yong; Wei, Yu Quan; Chen, Yu Zong

    2011-05-01

    Various in vitro and in-silico methods have been used for drug genotoxicity tests, which show limited genotoxicity (GT+) and non-genotoxicity (GT-) identification rates. New methods and combinatorial approaches have been explored for enhanced collective identification capability. The rates of in-silco methods may be further improved by significantly diversified training data enriched by the large number of recently reported GT+ and GT- compounds, but a major concern is the increased noise levels arising from high false-positive rates of in vitro data. In this work, we evaluated the effect of training data size and noise level on the performance of support vector machines (SVM) method known to tolerate high noise levels in training data. Two SVMs of different diversity/noise levels were developed and tested. H-SVM trained by higher diversity higher noise data (GT+ in any in vivo or in vitro test) outperforms L-SVM trained by lower noise lower diversity data (GT+ in in vivo or Ames test only). H-SVM trained by 4,763 GT+ compounds reported before 2008 and 8,232 GT- compounds excluding clinical trial drugs correctly identified 81.6% of the 38 GT+ compounds reported since 2008, predicted 83.1% of the 2,008 clinical trial drugs as GT-, and 23.96% of 168 K MDDR and 27.23% of 17.86M PubChem compounds as GT+. These are comparable to the 43.1-51.9% GT+ and 75-93% GT- rates of existing in-silico methods, 58.8% GT+ and 79% GT- rates of Ames method, and the estimated percentages of 23% in vivo and 31-33% in vitro GT+ compounds in the "universe of chemicals". There is a substantial level of agreement between H-SVM and L-SVM predicted GT+ and GT- MDDR compounds and the prediction from TOPKAT. SVM showed good potential in identifying GT+ compounds from large compound libraries based on higher diversity and higher noise training data.

  19. Effect of training data size and noise level on support vector machines virtual screening of genotoxic compounds from large compound libraries.

    PubMed

    Kumar, Pankaj; Ma, Xiaohua; Liu, Xianghui; Jia, Jia; Bucong, Han; Xue, Ying; Li, Ze Rong; Yang, Sheng Yong; Wei, Yu Quan; Chen, Yu Zong

    2011-05-01

    Various in vitro and in-silico methods have been used for drug genotoxicity tests, which show limited genotoxicity (GT+) and non-genotoxicity (GT-) identification rates. New methods and combinatorial approaches have been explored for enhanced collective identification capability. The rates of in-silco methods may be further improved by significantly diversified training data enriched by the large number of recently reported GT+ and GT- compounds, but a major concern is the increased noise levels arising from high false-positive rates of in vitro data. In this work, we evaluated the effect of training data size and noise level on the performance of support vector machines (SVM) method known to tolerate high noise levels in training data. Two SVMs of different diversity/noise levels were developed and tested. H-SVM trained by higher diversity higher noise data (GT+ in any in vivo or in vitro test) outperforms L-SVM trained by lower noise lower diversity data (GT+ in in vivo or Ames test only). H-SVM trained by 4,763 GT+ compounds reported before 2008 and 8,232 GT- compounds excluding clinical trial drugs correctly identified 81.6% of the 38 GT+ compounds reported since 2008, predicted 83.1% of the 2,008 clinical trial drugs as GT-, and 23.96% of 168 K MDDR and 27.23% of 17.86M PubChem compounds as GT+. These are comparable to the 43.1-51.9% GT+ and 75-93% GT- rates of existing in-silico methods, 58.8% GT+ and 79% GT- rates of Ames method, and the estimated percentages of 23% in vivo and 31-33% in vitro GT+ compounds in the "universe of chemicals". There is a substantial level of agreement between H-SVM and L-SVM predicted GT+ and GT- MDDR compounds and the prediction from TOPKAT. SVM showed good potential in identifying GT+ compounds from large compound libraries based on higher diversity and higher noise training data.

  20. Lead, Uranium, and Nickel Compound Data from the XAFS Library at the Stanford Synchrotron Radiation Laboratory (SSRL)

    DOE Data Explorer

    The x-ray absorption fine structure spectroscopy (XAFS) library at the Stanford Synchrotron Radiation Laboratory is intended to be a reference library of XAFS spectra for various lead, uranium, and nickel compounds. Compounds are organized by central atom and all spectra are transmission data. Molecular Environmental Science (MES) research at SSRL focuses on the fundamental interfacial, molecular- and nano-scale processes that control contaminant and nutrient cycling in the biosphere with the goal of elucidating global elemental cycles and anthropogenic influences on the environment. Key areas of investigation include the: (a) Structural chemistry of water and dissolved solutes, (b) Structural chemistry and reactivity of complex natural environmental materials with respect to heavy metals and metalloids (biominerals, Fe- and Mn-oxides, biofilms, and organic materials), (c) Reactions at environmental interfaces, including sorption, precipitation and dissolution processes that affect the bioavailability of heavy metals and other contaminants, and (d) Microbial transformations of metals and anions. SSRL-based MES research utilizes synchrotron-based x-ray absorption spectroscopy (XAS), x-ray diffraction (XRD), small-angle x-ray scattering (SAXS), x-ray standing wave (XSW) spectroscopy, and photoemission spectroscopy (PES) because of their unique capabilities to probe structure/composition relationships in complex, non-crystalline, and dilute materials. [copied from http://www-ssrl.slac.stanford.edu/mes/index.html

  1. Friendly strategy to prepare encoded one bead-one compound cyclic peptide library.

    PubMed

    Giudicessi, Silvana L; Gurevich-Messina, Juan M; Martínez-Ceron, María C; Erra-Balsells, Rosa; Albericio, Fernando; Cascone, Osvaldo; Camperi, Silvia A

    2013-10-14

    One bead-one peptide libraries allow the screening of suitable ligands for any target protein. Short cyclic peptides are ideal ligands for affinity chromatography because of their high affinity and selectivity for the target protein and stability against proteases. We designed a library synthesis strategy to facilitate the identification of cyclic peptides by MS consisting of (a) sequential incorporation of a mixture of Fmoc-Ala-OH and Fmoc-Asp[2-phenylisopropyl (OPp)]-OH (15:85) to Gly-oxymethylbenzamide-ChemMatrix (Gly-HMBA-CM) resin, (b) synthesis of the combinatorial library on the resin by the divide-couple-recombine method, (c) removal of OPp with 4% TFA, (d) peptide cyclization on solid phase through side-chain Asp and amino terminus, and (e) removal of side chain protecting groups with a 95% TFA cocktail. Peptides were cleaved from the beads with ammonia and the linear code was sequenced by MALDI-TOF MS/MS. The high capacity of ChemMatrix resin together with the sensitivity of MS allows code sequencing from a single bead.

  2. Discovery of nonsteroidal 17beta-hydroxysteroid dehydrogenase 1 inhibitors by pharmacophore-based screening of virtual compound libraries.

    PubMed

    Schuster, Daniela; Nashev, Lyubomir G; Kirchmair, Johannes; Laggner, Christian; Wolber, Gerhard; Langer, Thierry; Odermatt, Alex

    2008-07-24

    17Beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) plays a pivotal role in the local synthesis of the most potent estrogen estradiol. Its expression is a prognostic marker for the outcome of patients with breast cancer and inhibition of 17beta-HSD1 is currently under consideration for breast cancer prevention and treatment. We aimed to identify nonsteroidal 17beta-HSD1 inhibitor scaffolds by virtual screening with pharmacophore models built from crystal structures containing steroidal compounds. The most promising model was validated by comparing predicted and experimentally determined inhibitory activities of several flavonoids. Subsequently, a virtual library of nonsteroidal compounds was screened against the 3D pharmacophore. Analysis of 14 selected compounds yielded four that inhibited the activity of human 17beta-HSD1 (IC 50 below 50 microM). Specificity assessment of identified 17beta-HSD1 inhibitors emphasized the importance of including related short-chain dehydrogenase/reductase (SDR) members to analyze off-target effects. Compound 29 displayed at least 10-fold selectivity over the related SDR enzymes tested.

  3. A library of seleno-compounds and Leishmania species: Rising evidences towards novel agents.

    PubMed

    Martín-Montes, Álvaro; Plano, Daniel; Martín-Escolano, Rubén; Alcolea, Verónica; Díaz, Marta; Pérez-Silanes, Silvia; Espuelas, Socorro; Moreno, Esther; Marín, Clotilde; Gutiérrez-Sánchez, Ramón; Sanmartín, Carmen; Sánchez-Moreno, Manuel

    2017-03-20

    In vitro leishmanicidal activity of a series of forty-eight selenium derivatives, recently synthesized, was tested on Leishmania infantum and Leishmania braziliensis parasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of the tested compounds on J774.2 macrophage cells was also measured in order to establish their selectivity. Six of the tested compounds (8, 10, 11, 15, 45 and 48) showed selectivity indexes higher than those of the reference drug Glucantime for both Leishmania species; in the case of L. braziliensis, compound 20 was also remarkably selective. Moreover, infection rates and amastigote numbers per macrophage data showed that compounds 8, 10, 11, 15, 45 and 48 are the most active against both studied Leishmania species. The changes observed in the excretion product profile of parasites treated with these six compounds were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds were potent inhibitors of Fe-SOD in the two parasite species considered, whereas their impact on human CuZn-SOD was low. The high activity, low toxicity, stability, low cost of the starting materials and straightforward synthesis make these compounds appropriate molecules for the development of affordable anti-leishmanicidal agents.

  4. A support vector machines approach for virtual screening of active compounds of single and multiple mechanisms from large libraries at an improved hit-rate and enrichment factor.

    PubMed

    Han, L Y; Ma, X H; Lin, H H; Jia, J; Zhu, F; Xue, Y; Li, Z R; Cao, Z W; Ji, Z L; Chen, Y Z

    2008-06-01

    Support vector machines (SVM) and other machine-learning (ML) methods have been explored as ligand-based virtual screening (VS) tools for facilitating lead discovery. While exhibiting good hit selection performance, in screening large compound libraries, these methods tend to produce lower hit-rate than those of the best performing VS tools, partly because their training-sets contain limited spectrum of inactive compounds. We tested whether the performance of SVM can be improved by using training-sets of diverse inactive compounds. In retrospective database screening of active compounds of single mechanism (HIV protease inhibitors, DHFR inhibitors, dopamine antagonists) and multiple mechanisms (CNS active agents) from large libraries of 2.986 million compounds, the yields, hit-rates, and enrichment factors of our SVM models are 52.4-78.0%, 4.7-73.8%, and 214-10,543, respectively, compared to those of 62-95%, 0.65-35%, and 20-1200 by structure-based VS and 55-81%, 0.2-0.7%, and 110-795 by other ligand-based VS tools in screening libraries of >or=1 million compounds. The hit-rates are comparable and the enrichment factors are substantially better than the best results of other VS tools. 24.3-87.6% of the predicted hits are outside the known hit families. SVM appears to be potentially useful for facilitating lead discovery in VS of large compound libraries.

  5. DNA-Encoded Compound Libraries as Open Source: A Powerful Pathway to New Drugs.

    PubMed

    Lerner, Richard A; Brenner, Sydney

    2017-01-24

    "… We envisioned an iterative system where a unique DNA tag identifier that encoded the event was appended to each newly formed molecule. These vast collections of molecules are known today as DNA- encoded chemical libraries (DECLs), and allow scientists to do selections on the benchtop that previously required access to large and complex high-throughput screening centers …" Read more in the Guest Editorial by Richard A. Lerner and Sydney Brenner. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni

    PubMed Central

    Panic, Gordana; Vargas, Mireille; Scandale, Ivan; Keiser, Jennifer

    2015-01-01

    Background As plans to expand mass drug treatment campaigns to fight schistosomiasis form, worries about reliance on praziquantel as the sole available treatment motivate the investigation for novel antischistosomal compounds. Drug repurposing might be an inexpensive and effective source of novel antischistosomal leads. Methodology 1600 FDA approved compounds were first assayed against Schistosoma mansoni schistosomula at a concentration of 10 µM. Active compounds identified from this screen were advanced to the adult worm screen at 33.33 µM, followed by hit characterization. Leads with complementary pharmacokinetic and toxicity profiles were then selected for in vivo studies. Principal Findings The in vitro screen identified 121 and 36 compounds active against the schistosomula and adult stage, respectively. Further, in vitro characterization and comparison with already available pharmacokinetic and toxicity data identified 11 in vivo candidates. Doramectin (10 mg/kg) and clofazimine (400 mg/kg) were found to be active in vivo with worm burden reductions of 60.1% and 82.7%, respectively. Conclusions/Significance The work presented here expands the knowledge of antischistosomal properties of already approved compounds and underscores variations observed between target-based and phenotypic approaches and among laboratories. The two in vivo-active drugs identified in this study, doramectin and clofazimine are widely available and present as novel drug classes as starting points for further investigation. PMID:26230921

  7. Direct Phenotypic Screening in Mice: Identification of Individual, Novel Antinociceptive Compounds from a Library of 734 821 Pyrrolidine Bis-piperazines

    PubMed Central

    2015-01-01

    The hypothesis in the current study is that the simultaneous direct in vivo testing of thousands to millions of systematically arranged mixture-based libraries will facilitate the identification of enhanced individual compounds. Individual compounds identified from such libraries may have increased specificity and decreased side effects early in the discovery phase. Testing began by screening ten diverse scaffolds as single mixtures (ranging from 17 340 to 4 879 681 compounds) for analgesia directly in the mouse tail withdrawal model. The “all X” mixture representing the library TPI-1954 was found to produce significant antinociception and lacked respiratory depression and hyperlocomotor effects using the Comprehensive Laboratory Animal Monitoring System (CLAMS). The TPI-1954 library is a pyrrolidine bis-piperazine and totals 738 192 compounds. This library has 26 functionalities at the first three positions of diversity made up of 28 392 compounds each (26 × 26 × 42) and 42 functionalities at the fourth made up of 19 915 compounds each (26 × 26 × 26). The 120 resulting mixtures representing each of the variable four positions were screened directly in vivo in the mouse 55 °C warm-water tail-withdrawal assay (ip administration). The 120 samples were then ranked in terms of their antinociceptive activity. The synthesis of 54 individual compounds was then carried out. Nine of the individual compounds produced dose-dependent antinociception equivalent to morphine. In practical terms what this means is that one would not expect multiexponential increases in activity as we move from the all-X mixture, to the positional scanning libraries, to the individual compounds. Actually because of the systematic formatting one would typically anticipate steady increases in activity as the complexity of the mixtures is reduced. This is in fact what we see in the current study. One of the final individual compounds identified, TPI 2213-17, lacked significant

  8. Direct Phenotypic Screening in Mice: Identification of Individual, Novel Antinociceptive Compounds from a Library of 734,821 Pyrrolidine Bis-piperazines.

    PubMed

    Houghten, Richard A; Ganno, Michelle L; McLaughlin, Jay P; Dooley, Colette T; Eans, Shainnel O; Santos, Radleigh G; LaVoi, Travis; Nefzi, Adel; Welmaker, Greg; Giulianotti, Marc A; Toll, Lawrence

    2016-01-11

    The hypothesis in the current study is that the simultaneous direct in vivo testing of thousands to millions of systematically arranged mixture-based libraries will facilitate the identification of enhanced individual compounds. Individual compounds identified from such libraries may have increased specificity and decreased side effects early in the discovery phase. Testing began by screening ten diverse scaffolds as single mixtures (ranging from 17,340 to 4,879,681 compounds) for analgesia directly in the mouse tail withdrawal model. The "all X" mixture representing the library TPI-1954 was found to produce significant antinociception and lacked respiratory depression and hyperlocomotor effects using the Comprehensive Laboratory Animal Monitoring System (CLAMS). The TPI-1954 library is a pyrrolidine bis-piperazine and totals 738,192 compounds. This library has 26 functionalities at the first three positions of diversity made up of 28,392 compounds each (26 × 26 × 42) and 42 functionalities at the fourth made up of 19,915 compounds each (26 × 26 × 26). The 120 resulting mixtures representing each of the variable four positions were screened directly in vivo in the mouse 55 °C warm-water tail-withdrawal assay (ip administration). The 120 samples were then ranked in terms of their antinociceptive activity. The synthesis of 54 individual compounds was then carried out. Nine of the individual compounds produced dose-dependent antinociception equivalent to morphine. In practical terms what this means is that one would not expect multiexponential increases in activity as we move from the all-X mixture, to the positional scanning libraries, to the individual compounds. Actually because of the systematic formatting one would typically anticipate steady increases in activity as the complexity of the mixtures is reduced. This is in fact what we see in the current study. One of the final individual compounds identified, TPI 2213-17, lacked significant respiratory

  9. jCompoundMapper: An open source Java library and command-line tool for chemical fingerprints.

    PubMed

    Hinselmann, Georg; Rosenbaum, Lars; Jahn, Andreas; Fechner, Nikolas; Zell, Andreas

    2011-01-10

    The decomposition of a chemical graph is a convenient approach to encode information of the corresponding organic compound. While several commercial toolkits exist to encode molecules as so-called fingerprints, only a few open source implementations are available. The aim of this work is to introduce a library for exactly defined molecular decompositions, with a strong focus on the application of these features in machine learning and data mining. It provides several options such as search depth, distance cut-offs, atom- and pharmacophore typing. Furthermore, it provides the functionality to combine, to compare, or to export the fingerprints into several formats. We provide a Java 1.6 library for the decomposition of chemical graphs based on the open source Chemistry Development Kit toolkit. We reimplemented popular fingerprinting algorithms such as depth-first search fingerprints, extended connectivity fingerprints, autocorrelation fingerprints (e.g. CATS2D), radial fingerprints (e.g. Molprint2D), geometrical Molprint, atom pairs, and pharmacophore fingerprints. We also implemented custom fingerprints such as the all-shortest path fingerprint that only includes the subset of shortest paths from the full set of paths of the depth-first search fingerprint. As an application of jCompoundMapper, we provide a command-line executable binary. We measured the conversion speed and number of features for each encoding and described the composition of the features in detail. The quality of the encodings was tested using the default parametrizations in combination with a support vector machine on the Sutherland QSAR data sets. Additionally, we benchmarked the fingerprint encodings on the large-scale Ames toxicity benchmark using a large-scale linear support vector machine. The results were promising and could often compete with literature results. On the large Ames benchmark, for example, we obtained an AUC ROC performance of 0.87 with a reimplementation of the extended

  10. Combinatorial support vector machines approach for virtual screening of selective multi-target serotonin reuptake inhibitors from large compound libraries.

    PubMed

    Shi, Z; Ma, X H; Qin, C; Jia, J; Jiang, Y Y; Tan, C Y; Chen, Y Z

    2012-02-01

    Selective multi-target serotonin reuptake inhibitors enhance antidepressant efficacy. Their discovery can be facilitated by multiple methods, including in silico ones. In this study, we developed and tested an in silico method, combinatorial support vector machines (COMBI-SVMs), for virtual screening (VS) multi-target serotonin reuptake inhibitors of seven target pairs (serotonin transporter paired with noradrenaline transporter, H(3) receptor, 5-HT(1A) receptor, 5-HT(1B) receptor, 5-HT(2C) receptor, melanocortin 4 receptor and neurokinin 1 receptor respectively) from large compound libraries. COMBI-SVMs trained with 917-1951 individual target inhibitors correctly identified 22-83.3% (majority >31.1%) of the 6-216 dual inhibitors collected from literature as independent testing sets. COMBI-SVMs showed moderate to good target selectivity in misclassifying as dual inhibitors 2.2-29.8% (majority <15.4%) of the individual target inhibitors of the same target pair and 0.58-7.1% of the other 6 targets outside the target pair. COMBI-SVMs showed low dual inhibitor false hit rates (0.006-0.056%, 0.042-0.21%, 0.2-4%) in screening 17 million PubChem compounds, 168,000 MDDR compounds, and 7-8181 MDDR compounds similar to the dual inhibitors. Compared with similarity searching, k-NN and PNN methods, COMBI-SVM produced comparable dual inhibitor yields, similar target selectivity, and lower false hit rate in screening 168,000 MDDR compounds. The annotated classes of many COMBI-SVMs identified MDDR virtual hits correlate with the reported effects of their predicted targets. COMBI-SVM is potentially useful for searching selective multi-target agents without explicit knowledge of these agents.

  11. UNICON: A Powerful and Easy-to-Use Compound Library Converter.

    PubMed

    Sommer, Kai; Friedrich, Nils-Ole; Bietz, Stefan; Hilbig, Matthias; Inhester, Therese; Rarey, Matthias

    2016-06-27

    The accurate handling of different chemical file formats and the consistent conversion between them play important roles for calculations in complex cheminformatics workflows. Working with different cheminformatic tools often makes the conversion between file formats a mandatory step. Such a conversion might become a difficult task in cases where the information content substantially differs. This paper describes UNICON, an easy-to-use software tool for this task. The functionality of UNICON ranges from file conversion between standard formats SDF, MOL2, SMILES, PDB, and PDBx/mmCIF via the generation of 2D structure coordinates and 3D structures to the enumeration of tautomeric forms, protonation states, and conformer ensembles. For this purpose, UNICON bundles the key elements of the previously described NAOMI library in a single, easy-to-use command line tool.

  12. Application of high-throughput affinity-selection mass spectrometry for screening of chemical compound libraries in lead discovery.

    PubMed

    Zehender, Hartmut; Mayr, Lorenz M

    2007-02-01

    High-throughput screening of chemical libraries for compounds that interfere with a particular molecular target is among the most powerful methodologies applied in lead discovery at present. In this review, the authors describe a label-free, homogeneous, affinity-selection-based technology developed at Novartis, termed SpeedScreen, which is compared with similar technologies used for high-throughput screening in the pharmaceutical and biotechnology industries. The focus at present of SpeedScreen is twofold: first, this technology is applied to orphan genomic targets and to those targets that are non-tractable by a functional assay; second, this technology is applied complementary to the well-established traditional methodologies for the screening of molecular targets. In summary, the authors discuss the value of affinity-selection-based high-throughput screening as a complementary technology to the common functional screening platforms and the benefits as well as the limitations of this new technology are outlined.

  13. Combinatorial chemistry: libraries from libraries, the art of the diversity-oriented transformation of resin-bound peptides and chiral polyamides to low molecular weight acyclic and heterocyclic compounds.

    PubMed

    Nefzi, Adel; Ostresh, John M; Yu, Yongping; Yu, Jongping; Houghten, Richard A

    2004-05-28

    Combinatorial chemistry has deeply impacted the drug discovery process by accelerating the synthesis and screening of large numbers of compounds having therapeutic and/or diagnostic potential. These techniques offer unique enhancement in the potential identification of new and/or therapeutic candidates. Our efforts over the past 10 years in the design and diversity-oriented synthesis of low molecular weight acyclic and heterocyclic combinatorial libraries derived from amino acids, peptides, and/or peptidomimetics are described. Employing a "toolbox" of various chemical transformations, including alkylation, oxidation, reduction, acylation, and the use of a variety of multifunctional reagents, the "libraries from libraries" concept has enabled the continued development of an ever-expanding, structurally varied series of organic chemical libraries.

  14. Lead selection and characterization of antitubercular compounds using the Nested Chemical Library.

    PubMed

    Sipos, Anna; Pató, János; Székely, Rita; Hartkoorn, Ruben C; Kékesi, László; Őrfi, László; Szántai-Kis, Csaba; Mikušová, Katarína; Svetlíková, Zuzana; Korduláková, Jana; Nagaraja, Valakunja; Godbole, Adwait Anand; Bush, Natassja; Collin, Frédéric; Maxwell, Anthony; Cole, Stewart T; Kéri, György

    2015-06-01

    Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find novel antitubercular agents several approaches have been used in various institutions worldwide, including target-based approaches against several validated mycobacterial enzymes and phenotypic screens. We screened more than 17,000 compounds from Vichem's Nested Chemical Library™ using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and target-based assays with protein kinases PknA, PknB and PknG as well as other targets such as PimA and bacterial topoisomerases simultaneously. With the help of the target-based approach we have found very potent hits inhibiting the selected target enzymes, but good minimal inhibitory concentrations (MIC) against M. tuberculosis were not achieved. Focussing on the whole cell-based approach several potent hits were found which displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10 μM and were non-mutagenic, non-cytotoxic and the targets of some of the hits were also identified. The most active hits represented various scaffolds. Medicinal chemistry-based lead optimization was performed applying various strategies and, as a consequence, a series of novel potent compounds were synthesized. These efforts resulted in some effective potential antitubercular lead compounds which were confirmed in phenotypic assays.

  15. An efficient in silico screening method based on the protein-compound affinity matrix and its application to the design of a focused library for cytochrome P450 (CYP) ligands.

    PubMed

    Fukunishi, Yoshifumi; Hojo, Shinichi; Nakamura, Haruki

    2006-01-01

    A new method has been developed to design a focused library based on available active compounds using protein-compound docking simulations. This method was applied to the design of a focused library for cytochrome P450 (CYP) ligands, not only to distinguish CYP ligands from other compounds but also to identify the putative ligands for a particular CYP. Principal component analysis (PCA) was applied to the protein-compound affinity matrix, which was obtained by thorough docking calculations between a large set of protein pockets and chemical compounds. Each compound was depicted as a point in the PCA space. Compounds that were close to the known active compounds were selected as candidate hit compounds. A machine-learning technique optimized the docking scores of the protein-compound affinity matrix to maximize the database enrichment of the known active compounds, providing an optimized focused library.

  16. High-throughput screening of one-bead-one-compound libraries: identification of cyclic peptidyl inhibitors against calcineurin/NFAT interaction.

    PubMed

    Liu, Tao; Qian, Ziqing; Xiao, Qing; Pei, Dehua

    2011-09-12

    One-bead-one-compound (OBOC) libraries provide a powerful tool for drug discovery as well as biomedical research. However, screening a large number of beads/compounds (>1 million) and rank ordering the initial hits (which are covalently attached to a solid support) according to their potencies still post significant technical challenges. In this work, we have integrated some of the latest technical advances from our own as well as other laboratories to develop a general methodology for rapidly screening large OBOC libraries. The methodology has been applied to synthesize and screen a cyclic peptide library that features: (1) spatially segregated beads containing cyclic peptides on the surface layer and linear encoding peptides in their interior; (2) rapid on-bead screening of the library (>1 million) by a multistage procedure (magnetic bead sorting, enzyme-linked assay, and fluorescence based screening); (3) selective release of cyclic peptides from single positive beads for solution-phase determination of their binding affinities; and (4) hit identification by partial Edman degradation/mass spectrometry (PED/MS). Screening of the library against protein phosphatase calcineurin (Cn) identified a series of cyclic peptides that bind to the substrate-docking site for nuclear factor of activated T cells (NFAT) with K(D) values of ∼1 μM. Further improvement of the affinity and specificity of these compounds may lead to a new class of immunosuppressive agents that are more selective and therefore less toxic than cyclosporine A and FK506.

  17. Nature Bank and the Queensland Compound Library: unique international resources at the Eskitis Institute for Drug Discovery.

    PubMed

    Camp, David; Newman, Stuart; Pham, Ngoc B; Quinn, Ronald J

    2014-03-01

    The Eskitis Institute for Drug Discovery is home to two unique resources, Nature Bank and the Queensland Compound Library (QCL), that differentiate it from many other academic institutes pursuing chemical biology or early phase drug discovery. Nature Bank is a comprehensive collection of plants and marine invertebrates that have been subjected to a process which aligns downstream extracts and fractions with lead- and drug-like physicochemical properties. Considerable expertise in screening natural product extracts/fractions was developed at Eskitis over the last two decades. Importantly, biodiscovery activities have been conducted from the beginning in accordance with the UN Convention on Biological Diversity (CBD) to ensure compliance with all international and national legislative requirements. The QCL is a compound management and logistics facility that was established from public funds to augment previous investments in high throughput and phenotypic screening in the region. A unique intellectual property (IP) model has been developed in the case of the QCL to stimulate applied, basic and translational research in the chemical and life sciences by industry, non-profit, and academic organizations.

  18. Cdc25B Dual-Specificity Phosphatase Inhibitors Identified in a High-Throughput Screen of the NIH Compound Library

    PubMed Central

    Foster, Caleb A.; Tierno, Marni Brisson; Shun, Tong Ying; Shinde, Sunita N.; Paquette, William D.; Brummond, Kay M.; Wipf, Peter; Lazo, John S.

    2009-01-01

    Abstract The University of Pittsburgh Molecular Library Screening Center (Pittsburgh, PA) conducted a screen with the National Institutes of Health compound library for inhibitors of in vitro cell division cycle 25 protein (Cdc25) B activity during the pilot phase of the Molecular Library Screening Center Network. Seventy-nine (0.12%) of the 65,239 compounds screened at 10 μM met the active criterion of ≥50% inhibition of Cdc25B activity, and 25 (31.6%) of these were confirmed as Cdc25B inhibitors with 50% inhibitory concentration (IC50) values <50 μM. Thirteen of the Cdc25B inhibitors were represented by singleton chemical structures, and 12 were divided among four clusters of related structures. Thirteen (52%) of the Cdc25B inhibitor hits were quinone-based structures. The Cdc25B inhibitors were further characterized in a series of in vitro secondary assays to confirm their activity, to determine their phosphatase selectivity against two other dual-specificity phosphatases, mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-3, and to examine if the mechanism of Cdc25B inhibition involved oxidation and inactivation. Nine Cdc25B inhibitors did not appear to affect Cdc25B through a mechanism involving oxidation because they did not generate detectable amounts of H2O2 in the presence of dithiothreitol, and their Cdc25B IC50 values were not significantly affected by exchanging the dithiothreitol for β-mercaptoethanol or reduced glutathione or by adding catalase to the assay. Six of the nonoxidative hits were selective for Cdc25B inhibition versus MKP-1 and MKP-3, but only the two bisfuran-containing hits, PubChem substance identifiers 4258795 and 4260465, significantly inhibited the growth of human MBA-MD-435 breast and PC-3 prostate cancer cell lines. To confirm the structure and biological activity of 4260465, the compound was resynthesized along with two analogs. Neither of the substitutions to the two analogs was tolerated, and only the

  19. jCompoundMapper: An open source Java library and command-line tool for chemical fingerprints

    PubMed Central

    2011-01-01

    Background The decomposition of a chemical graph is a convenient approach to encode information of the corresponding organic compound. While several commercial toolkits exist to encode molecules as so-called fingerprints, only a few open source implementations are available. The aim of this work is to introduce a library for exactly defined molecular decompositions, with a strong focus on the application of these features in machine learning and data mining. It provides several options such as search depth, distance cut-offs, atom- and pharmacophore typing. Furthermore, it provides the functionality to combine, to compare, or to export the fingerprints into several formats. Results We provide a Java 1.6 library for the decomposition of chemical graphs based on the open source Chemistry Development Kit toolkit. We reimplemented popular fingerprinting algorithms such as depth-first search fingerprints, extended connectivity fingerprints, autocorrelation fingerprints (e.g. CATS2D), radial fingerprints (e.g. Molprint2D), geometrical Molprint, atom pairs, and pharmacophore fingerprints. We also implemented custom fingerprints such as the all-shortest path fingerprint that only includes the subset of shortest paths from the full set of paths of the depth-first search fingerprint. As an application of jCompoundMapper, we provide a command-line executable binary. We measured the conversion speed and number of features for each encoding and described the composition of the features in detail. The quality of the encodings was tested using the default parametrizations in combination with a support vector machine on the Sutherland QSAR data sets. Additionally, we benchmarked the fingerprint encodings on the large-scale Ames toxicity benchmark using a large-scale linear support vector machine. The results were promising and could often compete with literature results. On the large Ames benchmark, for example, we obtained an AUC ROC performance of 0.87 with a reimplementation of

  20. 1-/sup 11/C-D-glucose and related compounds

    SciTech Connect

    Shiue, C.Y.; Wolf, A.P.

    1982-01-26

    The novel compounds 1-/sup 11/C-D-glucose, 1-/sup 11/C-D-mannose, 1-/sup 11/C-D-galactose, 2-/sup 11/C-D-glucose, 2-/sup 11/C-D-mannose and 2-/sup 11/C-D-galactose which can be used in nuclear medicine to monitor the metabolism of glucose and galactose can be rapidly prepared by reaction of the appropriate aldose substrate with an alkali metal /sup 11/C-labeled cyanide followed by reduction with a Raney alloy in formic acid.

  1. 1-.sup.11 C-D-Glucose and related compounds

    DOEpatents

    Shiue, Chyng-Yann; Wolf, Alfred P.

    1984-03-27

    The novel compounds 1-.sup.11 C-D-glucose, 1-.sup.11 C-D-mannose, 1-.sup.11 C-D-galactose, 2-.sup.11 C-D-glucose, 2-.sup.11 C-D-mannose and 2-.sup.11 C-D-galactose which can be used in nuclear medicine to monitor the metabolism of glucose and galactose can be rapidly prepared by reaction of the appropriate aldose substrate with an alkali metal .sup.11 C-labeled cyanide followed by reduction with a Raney alloy in formic acid.

  2. Diverging DOS strategy using an allene-containing tryptophan scaffold and a library design that maximizes biologically relevant chemical space while minimizing the number of compounds.

    PubMed

    Painter, Thomas O; Wang, Lirong; Majumder, Supriyo; Xie, Xiang-Qun; Brummond, Kay M

    2011-03-14

    A diverging diversity-oriented synthesis (DOS) strategy using an allene-containing tryptophan as a key starting material was investigated. An allene-yne substituted derivative of tryptophan 12 gave indolylmethylazabicyclooctadiene 17 when subjected to a microwave-assisted allenic [2 + 2] cycloaddition reaction. This same tryptophan-derived precursor afforded an indolylmethyldihydrocyclopentapyridinone 14 when subjected to a rhodium(I)-catalyzed cyclocarbonylation reaction and an indolylmethylpyrrolidinocyclopentenones 16 when reacted with molybdenum hexacarbonyl. Construction of allenic tetrahydro-β-carboline scaffolds via a Pictet-Spengler reaction and subsequent silver(I)-catalyzed cycloisomerization afforded tetrahydroindolizinoindoles (21). Attachment of allene and alkyne groups to the tetrahydro-β-carboline, followed by a microwave-assisted allenic [2 + 2] cycloaddition reaction, provided tetrahydrocyclobutaindoloquinolizinones 24 and the tetrahydrocyclopentenone indolizinoindolone 26 when reacted with molybdenum hexacarbonyl. These six scaffolds were used as templates for the construction of a virtual library of 11 748 compounds employing 44 indoles, 12 aldehydes, and 51 alkynes. Diversity analyses using a combination of cell-based chemistry space computations using BCUT (Burden (B) CAS (C) Pearlman at the University of Texas (UT)) metrics and Tanimoto coefficient (Tc) similarity calculations using two-dimensional (2D) fingerprints showed that the compounds in the virtual library occupied new chemical space when compared to the 327,000 compounds in the molecular libraries small molecule repository (MLSMR). A subset of fifty-three compounds was identified from the virtual library using the DVS package of Sybyl 8.0; this subset represents the most diverse compounds within the chemical space defined by these compounds and will be synthesized and screened for biological activity.

  3. Structure-based tailoring of compound libraries for high-throughput screening: discovery of novel EphB4 kinase inhibitors.

    PubMed

    Kolb, Peter; Kipouros, Catherine Berset; Huang, Danzhi; Caflisch, Amedeo

    2008-10-01

    High-throughput docking is a computational tool frequently used to discover small-molecule inhibitors of enzymes or receptors of known three-dimensional structure. Because of the large number of molecules in chemical libraries, automatic procedures to prune multimillion compound collections are useful for high-throughput docking and necessary for in vitro screening. Here, we propose an anchor-based library tailoring approach (termed ALTA) to focus a chemical library by docking and prioritizing molecular fragments according to their binding energy which includes continuum electrostatics solvation. In principle, ALTA does not require prior knowledge of known inhibitors, but receptor-based pharmacophore information (hydrogen bonds with the hinge region) is additionally used here to identify molecules with optimal anchor fragments for the ATP-binding site of the EphB4 receptor tyrosine kinase. The 21,418 molecules of the focused library (from an initial collection of about 730,000) are docked into EphB4 and ranked by force-field-based energy including electrostatic solvation. Among the 43 compounds tested in vitro, eight molecules originating from two different anchors show low-micromolar activity in a fluorescence-based enzymatic assay. Four of them are active in a cell-based assay and are potential anti-angiogenic compounds.

  4. Identification and prioritization of novel anti-Wolbachia chemotypes from screening a 10,000-compound diversity library

    PubMed Central

    Johnston, Kelly L.; Cook, Darren A. N.; Berry, Neil G.; David Hong, W.; Clare, Rachel H.; Goddard, Megan; Ford, Louise; Nixon, Gemma L.; O’Neill, Paul M.; Ward, Stephen A.; Taylor, Mark J.

    2017-01-01

    Lymphatic filariasis and onchocerciasis are two important neglected tropical diseases (NTDs) that cause severe disability. Control efforts are hindered by the lack of a safe macrofilaricidal drug. Targeting the Wolbachia bacterial endosymbionts in these parasites with doxycycline leads to a macrofilaricidal outcome, but protracted treatment regimens and contraindications restrict its widespread implementation. The Anti-Wolbachia consortium aims to develop improved anti-Wolbachia drugs to overcome these barriers. We describe the first screening of a large, diverse compound library against Wolbachia. This whole-organism screen, streamlined to reduce bottlenecks, produced a hit rate of 0.5%. Chemoinformatic analysis of the top 50 hits led to the identification of six structurally diverse chemotypes, the disclosure of which could offer interesting avenues of investigation to other researchers active in this field. An example of hit-to-lead optimization is described to further demonstrate the potential of developing these high-quality hit series as safe, efficacious, and selective anti-Wolbachia macrofilaricides. PMID:28959730

  5. Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway

    PubMed Central

    Huang, Ruili; Sakamuru, Srilatha; Martin, Matt T.; Reif, David M.; Judson, Richard S.; Houck, Keith A.; Casey, Warren; Hsieh, Jui-Hua; Shockley, Keith R.; Ceger, Patricia; Fostel, Jennifer; Witt, Kristine L.; Tong, Weida; Rotroff, Daniel M.; Zhao, Tongan; Shinn, Paul; Simeonov, Anton; Dix, David J.; Austin, Christopher P.; Kavlock, Robert J.; Tice, Raymond R.; Xia, Menghang

    2014-01-01

    The U.S. Tox21 program has screened a library of approximately 10,000 (10K) environmental chemicals and drugs in three independent runs for estrogen receptor alpha (ERα) agonist and antagonist activity using two types of ER reporter gene cell lines, one with an endogenous full length ERα (ER-luc; BG1 cell line) and the other with a transfected partial receptor consisting of the ligand binding domain (ER-bla; ERα β-lactamase cell line), in a quantitative high-throughput screening (qHTS) format. The ability of the two assays to correctly identify ERα agonists and antagonists was evaluated using a set of 39 reference compounds with known ERα activity. Although both assays demonstrated adequate (i.e. >80%) predictivity, the ER-luc assay was more sensitive and the ER-bla assay more specific. The qHTS assay results were compared with results from previously published ERα binding assay data and showed >80% consistency. Actives identified from both the ER-bla and ER-luc assays were analyzed for structure-activity relationships (SARs) revealing known and potentially novel ERα active structure classes. The results demonstrate the feasibility of qHTS to identify environmental chemicals with the potential to interact with the ERα signaling pathway and the two different assay formats improve the confidence in correctly identifying these chemicals. PMID:25012808

  6. Synthetic library design.

    PubMed

    Huwe, Christoph M

    2006-08-01

    Compound libraries have an important role in the drug discovery process. Various computational methods are available as decision support tools for medicinal chemists involved in compound library synthesis programs. These methods can be used to assemble a flexible library design scheme consisting of a structure-based library design followed by property-biased library refinement and final selection according to structure-activity-relationship considerations.

  7. Synthesis and evaluation of N-methyl and S-methyl 11C-labeled 6-methylthio-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridines as radioligands for imaging beta-amyloid plaques in Alzheimer's disease.

    PubMed

    Cai, Lisheng; Liow, Jeih-San; Zoghbi, Sami S; Cuevas, Jessica; Baetas, Cesar; Hong, Jinsoo; Shetty, H Umesha; Seneca, Nicholas M; Brown, Amira K; Gladding, Robert; Temme, Sebastian S; Herman, Mary M; Innis, Robert B; Pike, Victor W

    2008-01-10

    6-Thiolato-substituted 2-(4'- N,N-dimethylamino)phenylimidazo[1,2- a]pyridines ( RS-IMPYs; 1- 4) were synthesized as candidates for labeling with carbon-11 ( t 1/2 = 20.4 min) and imaging of A beta plaques in living human brain using positron emission tomography (PET). K i values for binding of these ligands to Alzheimer's disease brain homogenates were measured in vitro against tritium-labeled 6 (Pittsburgh compound B). MeS-IMPY ( 3, K i = 7.93 nM) was labeled with carbon-11 at its S- or N-methyl position to give [ (11)C] 7 or [ (11)C] 8, respectively. After injection into rats, [ (11)C] 7 or [ (11)C] 8 gave moderately high brain uptakes of radioactivity followed by rapid washout to low levels. The ratio of radioactivity at maximal uptake to that at 60 min reached 18.7 for [ (11)C] 7. [ (11)C] 7 behaved similarly in mouse and monkey. [ (11)C] 7 also bound selectively to A beta plaques in post mortem human Alzheimer's disease brain. Although rapidly metabolized in rat by N-demethylation, [ (11)C] 7 was stable in rat brain homogenates. The ex vivo brain radiometabolites observed in rats have a peripheral origin. Overall, [ (11)C] 7 merits further evaluation in human subjects.

  8. Development of a system to evaluate compound identity, purity, and concentration in a single experiment and its application in quality assessment of combinatorial libraries and screening hits.

    PubMed

    Yurek, David A; Branch, Derek L; Kuo, Ming-Shang

    2002-01-01

    The development and use of a new assay system for the simultaneous determination of identity, purity, and concentration of sample components from combinatorial libraries produced by parallel synthesis are described. The system makes use of high-performance liquid chromatography with UV/vis photodiode array (PDA), evaporative light scattering (ELSD), chemiluminescent nitrogen (CLND), and time-of-flight mass spectrometer (TOFMS) detectors (HPLC-PDA-ELSD-CLND-TOFMS). Although these detectors have previously been utilized separately for the analysis of combinatorial chemistry libraries, the use of TOFMS along with CLND provides a synergistic combination enabling target and side-product structures to be identified and their concentrations and purities determined in a single experiment from a solution containing microgram levels of material. The CLND was found to give a linear response based on the number of moles of nitrogen present. Therefore, if the number of nitrogens per molecule is known, the concentration of each nitrogen-containing sample component may be determined utilizing an unrelated co-injected standard. A molecular formula for an impurity may often be calculated from the exact mass determined by the TOFMS and knowledge of the chemistry involved. Thus, if the sample components contain nitrogen, the concentration of every identified HPLC peak may be determined even in the absence of primary standards. This combination of detectors enabled the characterization of both target compounds and byproducts in combinatorial libraries, allowing the optimization of library synthetic procedures. This system was also used to survey the quality of libraries, enabling the selection of the best libraries for screening. This method also facilitated the characterization of samples from combinatorial libraries found as hits in high-throughput screening to establish the potency of the leads based on their actual concentration. In addition, concentrations and potencies of

  9. The discovery of macrocyclic XIAP antagonists from a DNA-programmed chemistry library, and their optimization to give lead compounds with in vivo antitumor activity.

    PubMed

    Seigal, Benjamin A; Connors, William H; Fraley, Andrew; Borzilleri, Robert M; Carter, Percy H; Emanuel, Stuart L; Fargnoli, Joseph; Kim, Kyoung; Lei, Ming; Naglich, Joseph G; Pokross, Matthew E; Posy, Shana L; Shen, Henry; Surti, Neha; Talbott, Randy; Zhang, Yong; Terrett, Nicholas K

    2015-03-26

    Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.

  10. Semi-automated high-throughput fluorescent intercalator displacement-based discovery of cytotoxic DNA binding agents from a large compound library.

    PubMed

    Glass, Lateca S; Bapat, Aditi; Kelley, Mark R; Georgiadis, Millie M; Long, Eric C

    2010-03-01

    High-throughput fluorescent intercalator displacement (HT-FID) was adapted to the semi-automated screening of a commercial compound library containing 60,000 molecules resulting in the discovery of cytotoxic DNA-targeted agents. Although commercial libraries are routinely screened in drug discovery efforts, the DNA binding potential of the compounds they contain has largely been overlooked. HT-FID led to the rapid identification of a number of compounds for which DNA binding properties were validated through demonstration of concentration-dependent DNA binding and increased thermal melting of A/T- or G/C-rich DNA sequences. Selected compounds were assayed further for cell proliferation inhibition in glioblastoma cells. Seven distinct compounds emerged from this screening procedure that represent structures unknown previously to be capable of targeting DNA leading to cell death. These agents may represent structures worthy of further modification to optimally explore their potential as cytotoxic anti-cancer agents. In addition, the general screening strategy described may find broader impact toward the rapid discovery of DNA targeted agents with biological activity. Copyright 2010 Elsevier Ltd. All rights reserved.

  11. Semi-automated high-throughput fluorescent intercalator displacement-based discovery of cytotoxic DNA binding agents from a large compound library

    PubMed Central

    Glass, LaTeca S.; Bapat, Aditi; Kelley, Mark R.; Georgiadis, Millie M.; Long, Eric C.

    2010-01-01

    High-throughput fluorescent intercalator displacement (HT-FID) was adapted to the semi-automated screening of a commercial compound library containing 60,000 molecules resulting in the discovery of cytotoxic DNA-targeted agents. Although commercial libraries are routinely screened in drug discovery efforts, the DNA binding potential of the compounds they contain has largely been overlooked. HT-FID led to the rapid identification of a number of compounds for which DNA binding properties were validated through demonstration of concentration-dependent DNA binding and increased thermal melting of A/T- or G/C-rich DNA sequences. Selected compounds were assayed further for cell proliferation inhibition in glioblastoma cells. Seven distinct compounds emerged from this screening procedure that represent structures unknown previously to be capable of targeting DNA leading to cell death. These agents may represent structures worthy of further modification to optimally explore their potential as cytotoxic anti-cancer agents. In addition, the general screening strategy described may find broader impact toward the rapid discovery of DNA targeted agents with biological activity. PMID:20144868

  12. Biodistribution and radiation dosimetry of 11C-labelled docetaxel in cancer patients

    PubMed Central

    Hendrikse, N. Harry; Smit, Egbert F.; Mooijer, Martien P. J.; Rijnders, Anneloes Y.; Gerritsen, Winald R.; van der Hoeven, Jacobus J. M.; Windhorst, Albert D.; Lammertsma, Adriaan A.; Lubberink, Mark

    2010-01-01

    Purpose Docetaxel is an important chemotherapeutic agent used for the treatment of several cancer types. As radiolabelled anticancer agents provide a potential means for personalized treatment planning, docetaxel was labelled with the positron emitter 11C. Non-invasive measurements of [11C]docetaxel uptake in organs and tumours may provide additional information on pharmacokinetics and pharmacodynamics of the drug docetaxel. The purpose of the present study was to determine the biodistribution and radiation absorbed dose of [11C]docetaxel in humans. Methods Biodistribution of [11C]docetaxel was measured in seven patients (five men and two women) with solid tumours using PET/CT. Venous blood samples were collected to measure activity in blood and plasma. Regions of interest (ROI) for various source organs were defined on PET (high [11C]docetaxel uptake) or CT (low [11C]docetaxel uptake). ROI data were used to generate time-activity curves and to calculate percentage injected dose and residence times. Radiation absorbed doses were calculated according to the MIRD method using OLINDA/EXM 1.0 software. Results Gall bladder and liver demonstrated high [11C]docetaxel uptake, whilst uptake in brain and normal lung was low. The percentage injected dose at 1 h in the liver was 47 ± 9%. [11C]docetaxel was rapidly cleared from plasma and no radiolabelled metabolites were detected. [11C]docetaxel uptake in tumours was moderate and highly variable between tumours. Conclusion The effective dose of [11C]docetaxel was 4.7 µSv/MBq. As uptake in normal lung is low, [11C]docetaxel may be a promising tracer for tumours in the thoracic region. PMID:20508935

  13. Compound

    NASA Astrophysics Data System (ADS)

    Suzumura, Akitoshi; Watanabe, Masaki; Nagasako, Naoyuki; Asahi, Ryoji

    2014-06-01

    Recently, Cu-based chalcogenides such as Cu3SbSe4, Cu2Se, and Cu2SnSe3 have attracted much attention because of their high thermoelectric performance and their common feature of very low thermal conductivity. However, for practical use, materials without toxic elements such as selenium are preferable. In this paper, we report Se-free Cu3SbS4 thermoelectric material and improvement of its figure of merit ( ZT) by chemical substitutions. Substitutions of 3 at.% Ag for Cu and 2 at.% Ge for Sb lead to significant reductions in the thermal conductivity by 37% and 22%, respectively. These substitutions do not sacrifice the power factor, thus resulting in enhancement of the ZT value. The sensitivity of the thermal conductivity to chemical substitutions in these compounds is discussed in terms of the calculated phonon dispersion and previously proposed models for Cu-based chalcogenides. To improve the power factor, we optimize the hole carrier concentration by substitution of Ge for Sb, achieving a power factor of 16 μW/cm K2 at 573 K, which is better than the best reported for Se-based Cu3SbSe4 compounds.

  14. UPLC-MS-ELSD-PDA as a powerful dereplication tool to facilitate compound identification from small molecule natural product libraries

    USDA-ARS?s Scientific Manuscript database

    Generation of natural product libraries containing column fractions, each with only a few small molecules, by a high throughput, automated fractionation system has made it possible to implement an improved dereplication strategy for selection and prioritization of hits in a natural product discovery...

  15. Li K-edge X-ray absorption near edge structure spectra for a library of lithium compounds applied in lithium batteries

    NASA Astrophysics Data System (ADS)

    Wang, Dongniu; Zuin, Lucia

    2017-01-01

    Lithium ion batteries (LIB) have achieved great success as energy supply systems in portable devices and in electrical vehicles. Identifying the local chemical structures of elemental lithium in lithium compounds is beneficial for improving understanding of battery components and performance. Herein, a library of Li K-edge X-ray absorption near edge structure (XANES) of lithium compounds relevant to Li-ion batteries is reported. Materials described include lithium metals (anode), Li-containing cathodes, electrolytes and solid electrolyte interphase (SEI). The results illustrate the characteristic spectral features stemming from the various electronic structures and chemical environment of lithium atoms for each and every possible battery component. XANES spectra of Sn based anode after discharging reveal the appearance of Li2CO3 on electrode surface. X-ray damage on sensitive lithium species is also assessed; the results reveal that more attention should be paid to irradiation effects to conduct XANES measurements for battery materials properly.

  16. Synthesis and preliminary biological evaluation of a small library of hybrid compounds based on Ugi isocyanide multicomponent reactions with a marine natural product scaffold.

    PubMed

    Avilés, Edward; Prudhomme, Jacques; Le Roch, Karine G; Franzblau, Scott G; Chandrasena, Kevin; Mayer, Alejandro M S; Rodríguez, Abimael D

    2015-11-15

    A mixture-based combinatorial library of five Ugi adducts (4-8) incorporating known antitubercular and antimalarial pharmacophores was successfully synthesized, starting from the naturally occurring diisocyanide 3, via parallel Ugi four-center three-component reactions (U-4C-3CR). The novel α-acylamino amides obtained were evaluated for their antiinfective potential against laboratory strains of Mycobacterium tuberculosis H37Rv and chloroquine-susceptible 3D7 Plasmodium falciparum. Interestingly, compounds 4-8 displayed potent in vitro antiparasitic activity with higher cytotoxicity in comparison to their diisocyanide precursor 3, with the best compound exhibiting an IC50 value of 3.6 nM. Additionally, these natural product inspired hybrids potently inhibited in vitro thromboxane B2 (TXB2) and superoxide anion (O2(-)) generation from Escherichia coli lipopolysaccharide (LPS)-activated rat neonatal microglia, with concomitant low short-term toxicity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. In vitro screen of a small molecule inhibitor drug library identifies multiple compounds that synergize with oncolytic myxoma virus against human brain tumor-initiating cells

    PubMed Central

    McKenzie, Brienne A.; Zemp, Franz J.; Pisklakova, Alexandra; Narendran, Aru; McFadden, Grant; Lun, Xueqing; Kenchappa, Rajappa S.; Kurz, Ebba U.; Forsyth, Peter A.

    2015-01-01

    Background Brain tumor-initiating cells (BTICs) are stem-like cells hypothesized to form a disease reservoir that mediates tumor recurrence in high-grade gliomas. Oncolytic virotherapy uses replication-competent viruses to target and kill malignant cells and has been evaluated in clinic for glioma therapy with limited results. Myxoma virus (MyxV) is a safe and highly effective oncolytic virus (OV) in conventional glioma models but, as seen with other OVs, is only modestly effective for patient-derived BTICs. The objective of this study was to determine whether MyxV treatment against human BTICs could be improved by combining chemotherapeutics and virotherapy. Methods A 73-compound library of drug candidates in clinical use or preclinical development was screened to identify compounds that sensitize human BTICs to MyxV treatment in vitro, and synergy was evaluated mathematically in lead compounds using Chou-Talalay analyses. The effects of combination therapy on viral gene expression and viral replication were also assessed. Results Eleven compounds that enhance MyxV efficacy were identified, and 6 were shown to synergize with the virus using Chou-Talalay analyses. Four of the synergistic compounds were shown to significantly increase viral gene expression, indicating a potential mechanism for synergy. Three highly synergistic compounds (axitinib, a VEGFR inhibitor; rofecoxib, a cyclooxygenase-2 inhibitor; and pemetrexed, a folate anti-metabolite) belong to classes of compounds that have not been previously shown to synergize with oncolytic viruses in vitro. Conclusions This study has identified multiple novel drug candidates that synergistically improve MyxV efficacy in a preclinical BTIC glioma model. PMID:25605818

  18. Comparison of LC/MS and SFC/MS for screening of a large and diverse library of pharmaceutically relevant compounds.

    PubMed

    Pinkston, J David; Wen, Dong; Morand, Kenneth L; Tirey, Debra A; Stanton, David T

    2006-11-01

    The search for greater speed of analysis has fueled many innovations in high-performance liquid chromatography (HPLC), such as the use of higher pressures and smaller stationary-phase particles, and the development of monolithic columns. Alternatively, one might alter the chromatographic mobile phase. The low viscosity and high diffusivity of the mobile phase in supercritical fluid chromatography (SFC) allows higher flow rates and lower pressure drops than is possible in traditional HPLC. In addition, SFC requires less organic, or aqueous-organic, solvent than LC (important in preparative-scale chromatography) and provides an alternative, normal-phase retention mechanism. But fluids that are commonly used as the main mobile-phase component in SFC, such as CO2, are relatively nonpolar. As a result, SFC is commonly believed to only be applicable to nonpolar and relatively low-polarity compounds. Here we build upon recent work with SFC of polar and ionic compounds and peptides, and we compare the LC/MS and SFC/MS of a diverse library of druglike compounds. A total of 75.0% of the library compounds were eluted and detected by SFC/MS, while 79.4% were eluted and detected by LC/MS. Some samples provided strong peaks that appeared to be related to the purported compound contained in the sample. When these were added to the "hits", the numbers rose to 86.7 and 89.9%, respectively. A total of 3.7% of the samples were observed by SFC/MS, but not by LC/MS, and 8.1% of the samples were observed by LC/MS, but not by SFC/MS. The only compound class that appeared to be consistently detected in LC/MS, but not in SFC/MS under our conditions, consisted of compounds containing a phosphate, a phosphonate, or a bisphosphonate. The SFC/MS method was at least as durable, reliable, and user-friendly as the LC/MS method. The APCI source required less cleaning during the SFC/MS separations than it did during LC/MS.

  19. Process automation toward ultra-high-throughput screening of combinatorial one-bead-one-compound (OBOC) peptide libraries.

    PubMed

    Cha, Junhoe; Lim, Jaehong; Zheng, Yiran; Tan, Sylvia; Ang, Yi Li; Oon, Jessica; Ang, Mei Wei; Ling, Jingjing; Bode, Marcus; Lee, Su Seong

    2012-06-01

    With an aim to develop peptide-based protein capture agents that can replace antibodies for in vitro diagnosis, an ultra-high-throughput screening strategy has been investigated by automating labor-intensive, time-consuming processes that are the construction of peptide libraries, sorting of positive beads, and peptide sequencing through analysis of tandem mass spectrometry data. Although instruments for automation, such as peptide synthesizers and automatic bead sorters, have been used in some groups, the overall process has not been well optimized to minimize time, cost, and efforts, as well as to maximize product quality and performance. Herein we suggest and explore several solutions to the existing problems with the automation of the key processes. The overall process optimization has been done successfully in orchestration with the technologies such as rapid cleavage of peptides from beads and semiautomatic peptide sequencing that we have developed previously. This optimization allowed one-round screening, from peptide library construction to peptide sequencing, to be completed within 4 to 5 days. We also successfully identified a 6-mer ligand for carcinoembryonic antigen-cell adhesion molecule 5 (CEACAM 5) through three-round screenings, including one-round screening of a focused library.

  20. Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening.

    PubMed

    Abdulla, Maha-Hamadien; Ruelas, Debbie S; Wolff, Brian; Snedecor, June; Lim, Kee-Chong; Xu, Fengyun; Renslo, Adam R; Williams, Janice; McKerrow, James H; Caffrey, Conor R

    2009-07-14

    Praziquantel (PZQ) is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance, it is prudent to search for novel therapeutics. Identification of anti-schistosomal chemicals has traditionally relied on phenotypic (whole organism) screening with adult worms in vitro and/or animal models of disease-tools that limit automation and throughput with modern microtiter plate-formatted compound libraries. A partially automated, three-component phenotypic screen workflow is presented that utilizes at its apex the schistosomular stage of the parasite adapted to a 96-well plate format with a throughput of 640 compounds per month. Hits that arise are subsequently screened in vitro against adult parasites and finally for efficacy in a murine model of disease. Two GO/NO GO criteria filters in the workflow prioritize hit compounds for tests in the animal disease model in accordance with a target drug profile that demands short-course oral therapy. The screen workflow was inaugurated with 2,160 chemically diverse natural and synthetic compounds, of which 821 are drugs already approved for human use. This affords a unique starting point to 'reposition' (re-profile) drugs as anti-schistosomals with potential savings in development timelines and costs. Multiple and dynamic phenotypes could be categorized for schistosomula and adults in vitro, and a diverse set of 'hit' drugs and chemistries were identified, including anti-schistosomals, anthelmintics, antibiotics, and neuromodulators. Of those hits prioritized for tests in the animal disease model, a number of leads were identified, one of which compares reasonably well with PZQ in significantly decreasing worm and egg burdens, and disease-associated pathology. Data arising from the three components of the screen are posted online as a community resource. To accelerate the identification of novel anti-schistosomals, we have developed a partially automated screen workflow that interfaces

  1. Drug Discovery for Schistosomiasis: Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening

    PubMed Central

    Wolff, Brian; Snedecor, June; Lim, Kee-Chong; Xu, Fengyun; Renslo, Adam R.; Williams, Janice; McKerrow, James H.; Caffrey, Conor R.

    2009-01-01

    Background Praziquantel (PZQ) is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance, it is prudent to search for novel therapeutics. Identification of anti-schistosomal chemicals has traditionally relied on phenotypic (whole organism) screening with adult worms in vitro and/or animal models of disease—tools that limit automation and throughput with modern microtiter plate-formatted compound libraries. Methods A partially automated, three-component phenotypic screen workflow is presented that utilizes at its apex the schistosomular stage of the parasite adapted to a 96-well plate format with a throughput of 640 compounds per month. Hits that arise are subsequently screened in vitro against adult parasites and finally for efficacy in a murine model of disease. Two GO/NO GO criteria filters in the workflow prioritize hit compounds for tests in the animal disease model in accordance with a target drug profile that demands short-course oral therapy. The screen workflow was inaugurated with 2,160 chemically diverse natural and synthetic compounds, of which 821 are drugs already approved for human use. This affords a unique starting point to ‘reposition’ (re-profile) drugs as anti-schistosomals with potential savings in development timelines and costs. Findings Multiple and dynamic phenotypes could be categorized for schistosomula and adults in vitro, and a diverse set of ‘hit’ drugs and chemistries were identified, including anti-schistosomals, anthelmintics, antibiotics, and neuromodulators. Of those hits prioritized for tests in the animal disease model, a number of leads were identified, one of which compares reasonably well with PZQ in significantly decreasing worm and egg burdens, and disease-associated pathology. Data arising from the three components of the screen are posted online as a community resource. Conclusions To accelerate the identification of novel anti-schistosomals, we have developed a partially

  2. Lending a helping hand, screening chemical libraries for compounds that enhance β-hexosaminidase A activity in GM2 gangliosidosis cells

    PubMed Central

    Tropak, Michael B.; Mahuran, Don

    2010-01-01

    Enzyme enhancement therapy is an emerging therapeutic approach that has the potential to treat many genetic diseases. Candidate diseases are those associated with a mutant protein that has difficulty folding and/or assembling into active oligomers in the endoplasmic reticulum. Many lysosomal storage diseases are candidates for enzyme enhancement therapy and have the additional advantage of requiring only 5–10% of normal enzyme levels to reduce and/or prevent substrate accumulation. Our long experience in working with the β-hexosaminidase (EC 3.2.1.52) isozymes system and its associated deficiencies (Tay-Sachs and Sandhoff disease) lead us to search for possible enzyme enhancement therapy-agents that could treat the chronic forms of these diseases which express 2–5% residual activity. Pharmacological chaperones are enzyme enhancement therapy-agents that are competitive inhibitors of the target enzyme. Each of the known β-hexosaminidase inhibitors (low μM IC50) increased mutant enzyme levels to ≥ 10% in chronic Tay-Sachs fibroblasts and also attenuated the thermo-denaturation of β-hexosaminidase. To expand the repertoire of pharmacological chaperones to more ‘drug-like’ compounds, we screened the Maybridge library of 50 000 compounds using a real-time assay for non-carbohydrate-based β-hexosaminidase inhibitors and identified several that functioned as pharmacological chaperones in patient cells. Two of these inhibitors had derivatives that had been tested in humans for other purposes. These observations lead us to screen the NINDS library of 1040 Food and Drug Administration approved compounds for pharmacological chaperones. Pyrimethamine, an antimalarial drug with well documented pharmacokinetics, was confirmed as a β-hexosaminidase pharmacological chaperone and compared favorably with our best carbohydrate-based pharmacological chaperone in patient cells with various mutant genotypes. PMID:17894780

  3. Antifungal testing and high-throughput screening of compound library against Geomyces destructans, the etiologic agent of geomycosis (WNS) in bats.

    PubMed

    Chaturvedi, Sudha; Rajkumar, Sunanda S; Li, Xiaojiang; Hurteau, Gregory J; Shtutman, Michael; Chaturvedi, Vishnu

    2011-03-02

    Bats in the northeastern U.S. are affected by geomycosis caused by the fungus Geomyces destructans (Gd). This infection is commonly referred to as White Nose Syndrome (WNS). Over a million hibernating bats have died since the fungus was first discovered in 2006 in a cave near Albany, New York. A population viability analysis conducted on little brown bats (Myotis lucifugus), one of six bat species infected with Gd, suggests regional extinction of this species within 20 years. The fungus Gd is a psychrophile ("cold loving"), but nothing is known about how it thrives at low temperatures and what pathogenic attributes allow it to infect bats. This study aimed to determine if currently available antifungal drugs and biocides are effective against Gd. We tested five Gd strains for their susceptibility to antifungal drugs and high-throughput screened (HTS) one representative strain with SpectrumPlus compound library containing 1,920 compounds. The results indicated that Gd is susceptible to a number of antifungal drugs at concentrations similar to the susceptibility range of human pathogenic fungi. Strains of Gd were susceptible to amphotericin B, fluconazole, itraconazole, ketoconazole and voriconazole. In contrast, very high MICs (minimum inhibitory concentrations) of flucytosine and echinocandins were needed for growth inhibition, which were suggestive of fungal resistance to these drugs. Of the 1,920 compounds in the library, a few caused 50%--to greater than 90% inhibition of Gd growth. A number of azole antifungals, a fungicide, and some biocides caused prominent growth inhibition. Our results could provide a theoretical basis for future strategies aimed at the rehabilitation of most affected bat species and for decontamination of Gd in the cave environment.

  4. High content image-based screening of a protease inhibitor library reveals compounds broadly active against Rift Valley fever virus and other highly pathogenic RNA viruses.

    PubMed

    Mudhasani, Rajini; Kota, Krishna P; Retterer, Cary; Tran, Julie P; Whitehouse, Chris A; Bavari, Sina

    2014-08-01

    High content image-based screening was developed as an approach to test a protease inhibitor small molecule library for antiviral activity against Rift Valley fever virus (RVFV) and to determine their mechanism of action. RVFV is the causative agent of severe disease of humans and animals throughout Africa and the Arabian Peninsula. Of the 849 compounds screened, 34 compounds exhibited ≥ 50% inhibition against RVFV. All of the hit compounds could be classified into 4 distinct groups based on their unique chemical backbone. Some of the compounds also showed broad antiviral activity against several highly pathogenic RNA viruses including Ebola, Marburg, Venezuela equine encephalitis, and Lassa viruses. Four hit compounds (C795-0925, D011-2120, F694-1532 and G202-0362), which were most active against RVFV and showed broad-spectrum antiviral activity, were selected for further evaluation for their cytotoxicity, dose response profile, and mode of action using classical virological methods and high-content imaging analysis. Time-of-addition assays in RVFV infections suggested that D011-2120 and G202-0362 targeted virus egress, while C795-0925 and F694-1532 inhibited virus replication. We showed that D011-2120 exhibited its antiviral effects by blocking microtubule polymerization, thereby disrupting the Golgi complex and inhibiting viral trafficking to the plasma membrane during virus egress. While G202-0362 also affected virus egress, it appears to do so by a different mechanism, namely by blocking virus budding from the trans Golgi. F694-1532 inhibited viral replication, but also appeared to inhibit overall cellular gene expression. However, G202-0362 and C795-0925 did not alter any of the morphological features that we examined and thus may prove to be good candidates for antiviral drug development. Overall this work demonstrates that high-content image analysis can be used to screen chemical libraries for new antivirals and to determine their mechanism of action and

  5. Developing a UHPLC-QTOF-MS and Automated Library Search Method for Screening Drugs and Toxic Compounds in Postmortem Specimens.

    PubMed

    Liu, Hsiu-Chuan; Yang, Chu-An; Liu, Ray H; Lin, Dong-Liang

    2017-03-24

    Screening and confirming the presence of drugs and toxic compounds in various matrices are important and challenging tasks routinely faced by forensic and clinical laboratories. Recent advances in the liquid chromatographic and mass spectrometric technologies have provided an opportunity for the development of more specific and effective approaches to achieve the "screening" and "confirmation" goals in a single analytical step. The objectives of this study are: (i) the establishment of an ultra-high performance liquid chromatographic, quadrupole time-of-flight mass spectrometric mass spectrometric and MS-MS spectral database, including 1,200 compounds of interest; and (ii) the development of an effective protocol, using this database and three searching algorithms, for general unknown screening of these compounds. The established database and protocol were evaluated through the analysis of 30 external proficiency test and 100 postmortem samples and found to be significantly more effective than the LC-IT-MS and GC-MS approaches previously established in our laboratory.

  6. Screening and identification of compounds with antiviral activity against hepatitis B virus using a safe compound library and novel real-time immune-absorbance PCR-based high throughput system

    PubMed Central

    Lamontagne, Jason; Mills, Courtney; Mao, Richeng; Goddard, Cally; Cai, Dawei; Guo, Haitao; Cuconati, Andy; Block, Timothy; Lu, Xuanyong

    2013-01-01

    There are now 7 nucleoside/tide analogues, along with interferon-α, that are approved by the FDA for the management of chronic hepatitis B virus (HBV) infection, a disease affecting hundreds of millions of people worldwide. These medications, however, are limited in usefulness, and significant side effects and the emergence of viral escape mutants make the development of novel and updated therapeutics a pressing need in the treatment of HBV. With this in mind, a library containing 2,000 compounds already known to be safe in both humans and mice with known mechanisms of action in mammalian cells were tested for the possibility of either antiviral activity against HBV or selective toxicity in HBV producing cell lines. A modified real-time immune-absorbance-polymerase chain reaction (IA-PCR) assay was developed for this screen, utilizing cells that produce and secrete intact HBV virions. In this procedure, viral particles are first captured by an anti-HBs antibody immobilized on a plate. The viral load is subsequently assessed by real-time PCR directly on captured particles. Using this assay, eight compounds were shown to consistently reduce the amount of secreted HBV viral particles in the culture medium under conditions that had no detectable impact on cell viability. Two compounds, proparacaine and chlorophyllide, were shown to reduce HBV levels 4- to 6-fold with an IC50 of 1 and 1.5μM respectively, and were selected for further study. The identification of these compounds as promising antiviral drug candidates against HBV, despite a lack of previous recognition of HBV antiviral activity, supports the validity and utility of testing known compounds for “off- pathogen target” activity against HBV, and also validates this IA-PCR assay as an important tool for the detection of anti-viral activity against enveloped viruses. PMID:23415884

  7. Screening and identification of compounds with antiviral activity against hepatitis B virus using a safe compound library and novel real-time immune-absorbance PCR-based high throughput system.

    PubMed

    Lamontagne, Jason; Mills, Courtney; Mao, Richeng; Goddard, Cally; Cai, Dawei; Guo, Haitao; Cuconati, Andy; Block, Timothy; Lu, Xuanyong

    2013-04-01

    There are now seven nucleoside/tide analogues, along with interferon-α, that are approved by the FDA for the management of chronic hepatitis B virus (HBV) infection, a disease affecting hundreds of millions of people worldwide. These medications, however, are limited in usefulness, and significant side effects and the emergence of viral escape mutants make the development of novel and updated therapeutics a pressing need in the treatment of HBV. With this in mind, a library containing 2000 compounds already known to be safe in both humans and mice with known mechanisms of action in mammalian cells were tested for the possibility of either antiviral activity against HBV or selective toxicity in HBV producing cell lines. A modified real-time immune-absorbance-polymerase chain reaction (IA-PCR) assay was developed for this screen, utilizing cells that produce and secrete intact HBV virions. In this procedure, viral particles are first captured by an anti-HBs antibody immobilized on a plate. The viral load is subsequently assessed by real-time PCR directly on captured particles. Using this assay, eight compounds were shown to consistently reduce the amount of secreted HBV viral particles in the culture medium under conditions that had no detectable impact on cell viability. Two compounds, proparacaine and chlorophyllide, were shown to reduce HBV levels 4- to 6-fold with an IC₅₀ of 1 and 1.5 μM, respectively, and were selected for further study. The identification of these compounds as promising antiviral drug candidates against HBV, despite a lack of previous recognition of HBV antiviral activity, supports the validity and utility of testing known compounds for "off-pathogen target" activity against HBV, and also validates this IA-PCR assay as an important tool for the detection of anti-viral activity against enveloped viruses. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. Application of parallel liquid chromatography/mass spectrometry for high throughput microsomal stability screening of compound libraries.

    PubMed

    Xu, Rongda; Nemes, Csaba; Jenkins, Kelly M; Rourick, Robyn A; Kassel, Daniel B; Liu, Charles Z C

    2002-02-01

    Solution-phase and solid-phase parallel synthesis and high throughput screening have enabled biologically active and selective compounds to be identified at an unprecedented rate. The challenge has been to convert these hits into viable development candidates. To accelerate the conversion of these hits into lead development candidates, early assessment of the physicochemical and pharmacological properties of these compounds is being made. In particular, in vitro absorption, distribution, metabolism, and elimination (ADME) assays are being conducted at earlier and earlier stages of discovery with the goal of reducing the attrition rate of these potential drug candidates as they progress through development. In this report, we present an eight-channel parallel liquid chromatography/mass spectrometry (LC/MS) system in combination with custom Visual Basic and Applescript automated data processing applications for high throughput early ADME. The parallel LC/MS system was configured with one set of gradient LC pumps and an eight-channel multiple probe autosampler. The flow was split equivalently into eight streams before the multiple probe autosampler and recombined after the eight columns and just prior to the mass spectrometer ion source. The system was tested for column-to-column variation and for reproducibility over a 17 h period (approximately 500 injections per column). The variations in retention time and peak area were determined to be less than 2 and 10%, respectively, in both tests. The parallel LC/MS system described permits time-course microsomal incubations (t(o), t5, t15, t30) to be measured in triplicate and enables estimations of t 1/2 microsomal stability. The parallel LC/MS system is capable of analyzing up to 240 samples per hour and permits the complete profiling up to two microtiter plates of compounds per day (i.e., 176 test substrate compounds + sixteen controls).

  9. Managing, profiling and analyzing a library of 2.6 million compounds gathered from 32 chemical providers.

    PubMed

    Monge, Aurélien; Arrault, Alban; Marot, Christophe; Morin-Allory, Luc

    2006-08-01

    The data for 3.8 million compounds from structural databases of 32 providers were gathered and stored in a single chemical database. Duplicates are removed using the IUPAC International Chemical Identifier. After this, 2.6 million compounds remain. Each database and the final one were studied in term of uniqueness, diversity, frameworks, 'drug-like' and 'lead-like' properties. This study also shows that there are more than 87 000 frameworks in the database. It contains 2.1 million 'drug-like' molecules among which, more than one million are 'lead-like'. This study has been carried out using 'ScreeningAssistant', a software dedicated to chemical databases management and screening sets generation. Compounds are stored in a MySQL database and all the operations on this database are carried out by Java code. The druglikeness and leadlikeness are estimated with 'in-house' scores using functions to estimate convenience to properties; unicity using the InChI code and diversity using molecular frameworks and fingerprints. The software has been conceived in order to facilitate the update of the database. 'ScreeningAssistant' is freely available under the GPL license.

  10. Phenotypic screening of a library of compounds against metastatic and non-metastatic clones of a canine mammary gland tumour cell line.

    PubMed

    Saeki, K; Watanabe, M; Michishita, M; Tsuboi, M; Sugano, S; Yoshitake, R; Murai, K; Tanaka, Y; Ong, S M; Saito, T; Matsumoto, K; Fujita, N; Nishimura, R; Nakagawa, T

    2015-08-01

    Metastases are associated with a poor prognosis for canine mammary gland tumours (CMGTs). Metastatic and non-metastatic clones were isolated previously from a single malignant CMGT cell line. The difference in metastatic potential between the two cell lines was hypothesised to be associated with distinct cellular signalling. The aim of this study was to screen for compounds that specifically target metastatic cells in order to improve CMGT therapeutic outcomes. The two clonal cell lines were characterised by transcriptome analysis and their sensitivity to a library of 291 different compounds was compared. The metastatic clone exhibited elevated expression of molecules associated with degradation of the extracellular matrix, epithelial-mesenchymal transition and cancer stem cell phenotype. This was confirmed using a matrigel invasion assay and by assessment of aldehyde dehydrogenase activity. The mitochondrial respiratory chain complex inhibitors (MRCIs; rotenone, antimycin and oligomycin) significantly inhibited the growth of the metastatic clone. Although MRCIs similarly depleted mitochondrial ATP in both clones, the subsequent cellular response was different, with toxicity to the metastatic clone being independent of AMP-activated protein kinase activity. The results of this study suggest a potential utility of MRCIs as anti-tumour agents against metastatic CMGTs. Further studies are needed to investigate the clinical utility of MRCIs and to determine the association between MRCI sensitivity and malignancy.

  11. Quantum Efficiency and Bandgap Analysis for Combinatorial Photovoltaics: Sorting Activity of Cu–O Compounds in All-Oxide Device Libraries

    PubMed Central

    2014-01-01

    All-oxide-based photovoltaics (PVs) encompass the potential for extremely low cost solar cells, provided they can obtain an order of magnitude improvement in their power conversion efficiencies. To achieve this goal, we perform a combinatorial materials study of metal oxide based light absorbers, charge transporters, junctions between them, and PV devices. Here we report the development of a combinatorial internal quantum efficiency (IQE) method. IQE measures the efficiency associated with the charge separation and collection processes, and thus is a proxy for PV activity of materials once placed into devices, discarding optical properties that cause uncontrolled light harvesting. The IQE is supported by high-throughput techniques for bandgap fitting, composition analysis, and thickness mapping, which are also crucial parameters for the combinatorial investigation cycle of photovoltaics. As a model system we use a library of 169 solar cells with a varying thickness of sprayed titanium dioxide (TiO2) as the window layer, and covarying thickness and composition of binary compounds of copper oxides (Cu–O) as the light absorber, fabricated by Pulsed Laser Deposition (PLD). The analysis on the combinatorial devices shows the correlation between compositions and bandgap, and their effect on PV activity within several device configurations. The analysis suggests that the presence of Cu4O3 plays a significant role in the PV activity of binary Cu–O compounds. PMID:24410367

  12. Rapid screening and confirmation of drugs and toxic compounds in biological specimens using liquid chromatography/ion trap tandem mass spectrometry and automated library search.

    PubMed

    Liu, Hsiu-Chuan; Liu, Ray H; Lin, Dong-Liang; Ho, Hsiu-O

    2010-01-01

    Recent advances in liquid chromatography/tandem mass spectrometry (LC/MS/MS) technology have provided an opportunity for the development of more specific approaches to achieve the 'screen' and 'confirmation' goals in a single analytical step. For this purpose, this study adapts the electrospray ionization ion trap LC/MS/MS instrumentation (LC/ESI-MS/MS) for the screening and confirmation of over 800 drugs and toxic compounds in biological specimens. Liquid-liquid and solid-phase extraction protocols were coupled to LC/ESI-MS/MS using a 1.8-microm particle size analytical column operated at 50 degrees C. Gradient elution of the analytes was conducted using a solvent system composed of methanol and water containing 0.1% formic acid. Positive-ion ESI-MS/MS spectra and retention times for each of the 800 drugs and toxic compounds were first established using 1-10 microg/mL standard solutions. This spectra and retention time information was then transferred to the library and searched by the identification algorithm for the confirmation of compounds found in test specimens - based on retention time matches and scores of fit, reverse fit, and purity resulting from the searching process. The established method was found highly effective when applied to the analyses of postmortem specimens (blood, urine, and hair) and external proficiency test samples provided by the College of American Pathology (CAP). The development of this approach has significantly improved the efficiency of our routine laboratory operation that was based on a two-step (immunoassay and GC/MS) approach in the past.

  13. Screening of an FDA-Approved Compound Library Identifies Four Small-Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Replication in Cell Culture

    PubMed Central

    de Wilde, Adriaan H.; Jochmans, Dirk; Posthuma, Clara C.; Zevenhoven-Dobbe, Jessika C.; van Nieuwkoop, Stefan; Bestebroer, Theo M.; van den Hoogen, Bernadette G.

    2014-01-01

    Coronaviruses can cause respiratory and enteric disease in a wide variety of human and animal hosts. The 2003 outbreak of severe acute respiratory syndrome (SARS) first demonstrated the potentially lethal consequences of zoonotic coronavirus infections in humans. In 2012, a similar previously unknown coronavirus emerged, Middle East respiratory syndrome coronavirus (MERS-CoV), thus far causing over 650 laboratory-confirmed infections, with an unexplained steep rise in the number of cases being recorded over recent months. The human MERS fatality rate of ∼30% is alarmingly high, even though many deaths were associated with underlying medical conditions. Registered therapeutics for the treatment of coronavirus infections are not available. Moreover, the pace of drug development and registration for human use is generally incompatible with strategies to combat emerging infectious diseases. Therefore, we have screened a library of 348 FDA-approved drugs for anti-MERS-CoV activity in cell culture. If such compounds proved sufficiently potent, their efficacy might be directly assessed in MERS patients. We identified four compounds (chloroquine, chlorpromazine, loperamide, and lopinavir) inhibiting MERS-CoV replication in the low-micromolar range (50% effective concentrations [EC50s], 3 to 8 μM). Moreover, these compounds also inhibit the replication of SARS coronavirus and human coronavirus 229E. Although their protective activity (alone or in combination) remains to be assessed in animal models, our findings may offer a starting point for treatment of patients infected with zoonotic coronaviruses like MERS-CoV. Although they may not necessarily reduce viral replication to very low levels, a moderate viral load reduction may create a window during which to mount a protective immune response. PMID:24841269

  14. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture.

    PubMed

    de Wilde, Adriaan H; Jochmans, Dirk; Posthuma, Clara C; Zevenhoven-Dobbe, Jessika C; van Nieuwkoop, Stefan; Bestebroer, Theo M; van den Hoogen, Bernadette G; Neyts, Johan; Snijder, Eric J

    2014-08-01

    Coronaviruses can cause respiratory and enteric disease in a wide variety of human and animal hosts. The 2003 outbreak of severe acute respiratory syndrome (SARS) first demonstrated the potentially lethal consequences of zoonotic coronavirus infections in humans. In 2012, a similar previously unknown coronavirus emerged, Middle East respiratory syndrome coronavirus (MERS-CoV), thus far causing over 650 laboratory-confirmed infections, with an unexplained steep rise in the number of cases being recorded over recent months. The human MERS fatality rate of ∼ 30% is alarmingly high, even though many deaths were associated with underlying medical conditions. Registered therapeutics for the treatment of coronavirus infections are not available. Moreover, the pace of drug development and registration for human use is generally incompatible with strategies to combat emerging infectious diseases. Therefore, we have screened a library of 348 FDA-approved drugs for anti-MERS-CoV activity in cell culture. If such compounds proved sufficiently potent, their efficacy might be directly assessed in MERS patients. We identified four compounds (chloroquine, chlorpromazine, loperamide, and lopinavir) inhibiting MERS-CoV replication in the low-micromolar range (50% effective concentrations [EC(50)s], 3 to 8 μM). Moreover, these compounds also inhibit the replication of SARS coronavirus and human coronavirus 229E. Although their protective activity (alone or in combination) remains to be assessed in animal models, our findings may offer a starting point for treatment of patients infected with zoonotic coronaviruses like MERS-CoV. Although they may not necessarily reduce viral replication to very low levels, a moderate viral load reduction may create a window during which to mount a protective immune response.

  15. Losing Libraries, Saving Libraries

    ERIC Educational Resources Information Center

    Miller, Rebecca

    2010-01-01

    This summer, as public libraries continued to get budget hit after budget hit across the country, several readers asked for a comprehensive picture of the ravages of the recession on library service. In partnership with 2010 Movers & Shakers Laura Solomon and Mandy Knapp, Ohio librarians who bought the Losing Libraries domain name,…

  16. Losing Libraries, Saving Libraries

    ERIC Educational Resources Information Center

    Miller, Rebecca

    2010-01-01

    This summer, as public libraries continued to get budget hit after budget hit across the country, several readers asked for a comprehensive picture of the ravages of the recession on library service. In partnership with 2010 Movers & Shakers Laura Solomon and Mandy Knapp, Ohio librarians who bought the Losing Libraries domain name,…

  17. 1-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as novel selective HIV integrase inhibitors obtained via privileged substructure-based compound libraries.

    PubMed

    Gao, Ping; Zhang, Lingzi; Sun, Lin; Huang, Tianguang; Tan, Jing; Zhang, Jian; Zhou, Zhongxia; Zhao, Tong; Menéndez-Arias, Luis; Pannecouque, Christophe; Clercq, Erik De; Zhan, Peng; Liu, Xinyong

    2017-10-15

    A small library containing 3-hydroxyquinazoline-2,4(1H,3H)-dione and 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one scaffolds was obtained via the copper(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction and evaluated for their anti-HIV activity in MT-4 cells. Among the synthesized compounds, several 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one derivatives showed remarkable anti-HIV potency with EC50 values ranging from 0.92 to 26.85µM. The most active one, IIA-2, also showed remarkable and selective potency against HIV type 1 integrase (IN). To the best of our knowledge, this is the first report showing that 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones are selective HIV IN inhibitors. Preliminary structure-activity relationship (SAR) studies suggested that the divalent metal ion chelators and the nature and position of substituents around the core are important for antiviral potency. Molecular modeling has been used to predict the binding site of the pyrido[2,3-d]pyrimidin-2(1H)-one core in HIV type 1 IN and suggestions are made for improvement of its inhibitory activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Evaluation of a new preparative supercritical fluid chromatography system for compound library purification: the TharSFC SFC-MS Prep-100 system.

    PubMed

    Ebinger, Katalin; Weller, Harold N; Kiplinger, Jeffrey; Lefebvre, Paul

    2011-06-01

    Preparative HPLC-MS is often the method of choice for purification of small amounts (<100mg) of diverse new molecules, such as compound libraries for drug discovery. The method is robust, well proven, and widely applicable. In contrast, preparative supercritical fluid chromatography coupled with mass spectrometry (SFC-MS) has seen only slow acceptance for the same application--despite some potential scientific and economic advantages. One of the reasons for slow adoption of SFC-MS is the lack of well-proven, robust, and commercially available instrumentation. In early 2009, TharSFC (a Waters Company, Pittsburgh, PA) introduced a new fully integrated system for preparative SFC-MS: The SFC-MS Prep-100. We report herein an objective evaluation of the SFC-MS Prep-100, including tests for pump and autosampler performance, sample recovery, sample carryover, fraction triggering, detector/fraction collector synchronization, and overall robustness. Our results suggest that the SFC-MS Prep-100 represents a significant advance over previous generation instrumentation.

  19. Identification of a small molecule inhibitor of importin beta mediated nuclear import by confocal on-bead screening of tagged one-bead one-compound libraries

    PubMed Central

    Hintersteiner, Martin; Ambrus, Géza; Bednenko, Janna; Schmied, Mario; Knox, Andrew J.S.; Gstach, Hubert; Seifert, Jan-Marcus; Singer, Eric L.; Gerace, Larry; Auer, Manfred

    2010-01-01

    In eukaryotic cells, proteins and RNA are transported between the nucleus and the cytoplasm by nuclear import and export receptors. Over the past decade, small molecules that inhibit the nuclear export receptor CRM1 have been identified, most notably leptomycin B. However, up to now no small molecule inhibitors of nuclear import have been described. Here we have used our automated Confocal Nanoscanning and bead picking method (CONA) for on-bead screening of a one bead/one compound library to identify the first such import inhibitor, karyostatin 1A. Karyostatin 1A binds importin β with high nanomolar affinity and specifically inhibits importin α/β mediated nuclear import at low micromolar concentrations in vitro and in living cells, without perturbing transportin mediated nuclear import or CRM1 mediated nuclear export. Surface plasmon resonance binding experiments suggest that karyostatin 1A acts by disrupting the interaction between importin β and the GTPase Ran. As a selective inhibitor of the importin α/β import pathway, karyostatin 1A will provide a valuable tool for future studies of nucleocytoplasmic trafficking. PMID:20677820

  20. Jeffamine derivatized TentaGel beads and poly(dimethylsiloxane) microbead cassettes for ultrahigh-throughput in situ releasable solution-phase cell-based screening of one-bead-one-compound combinatorial small molecule libraries.

    PubMed

    Townsend, Jared B; Shaheen, Farzana; Liu, Ruiwu; Lam, Kit S

    2010-09-13

    A method to efficiently immobilize and partition large quantities of microbeads in an array format in microfabricated poly(dimethylsiloxane) (PDMS) cassette for ultrahigh-throughput in situ releasable solution-phase cell-based screening of one-bead-one-compound (OBOC) combinatorial libraries is described. Commercially available Jeffamine triamine T-403 (∼440 Da) was derivatized such that two of its amino groups were protected by Fmoc and the remaining amino group capped with succinic anhydride to generate a carboxyl group. This resulting trifunctional hydrophilic polymer was then sequentially coupled two times to the outer layer of topologically segregated bilayer TentaGel (TG) beads with solid phase peptide synthesis chemistry resulting in beads with increased loading capacity, hydrophilicity, and porosity at the outer layer. We have found that such bead configuration can facilitate ultrahigh-throughput in situ releasable solution-phase screening of OBOC libraries. An encoded releasable OBOC small molecule library was constructed on Jeffamine derivatized TG beads with library compounds tethered to the outer layer via a disulfide linker and coding tags in the interior of the beads. Compound-beads could be efficiently loaded (5-10 min) into a 5 cm diameter Petri dish containing a 10,000-well PDMS microbead cassette, such that over 90% of the microwells were each filled with only one compound-bead. Jurkat T-lymphoid cancer cells suspended in Matrigel were then layered over the microbead cassette to immobilize the compound-beads. After 24 h of incubation at 37 °C, dithiothreitol was added to trigger the release of library compounds. Forty-eight hours later, MTT reporter assay was used to identify regions of reduced cell viability surrounding each positive bead. From a total of about 20,000 beads screened, 3 positive beads were detected and physically isolated for decoding. A strong consensus motif was identified for these three positive compounds. These compounds

  1. Creating Library Spaces: Libraries 2040.

    ERIC Educational Resources Information Center

    Bruijnzeels, Rob

    This paper suggests that by 2004, the traditional public libraries will have ceased to exist and new, attractive future libraries will have taken their place. The Libraries 2040 project of the Netherlands is initiating seven different libraries of the future. The Brabant library is the "ultimate library of the future" for the Dutch…

  2. Library Computing.

    ERIC Educational Resources Information Center

    Library Journal, 1985

    1985-01-01

    This special supplement to "Library Journal" and "School Library Journal" includes articles on technological dependency, promise of computers for reluctant readers, copyright and database downloading, access to neighborhood of Mister Rogers, library acquisitions, circulating personal computers, "microcomputeritis,"…

  3. Increased Diversity of Libraries from Libraries: Chemoinformatic Analysis of Bis-Diazacyclic Libraries

    PubMed Central

    López-Vallejo, Fabian; Nefzi, Adel; Bender, Andreas; Owen, John R.; Nabney, Ian T.; Houghten, Richard A.; Medina-Franco, Jose L.

    2011-01-01

    Combinatorial libraries continue to play a key role in drug discovery. To increase structural diversity, several experimental methods have been developed. However, limited efforts have been performed so far to quantify the diversity of the broadly used diversity-oriented synthetic (DOS) libraries. Herein we report a comprehensive characterization of 15 bis-diazacyclic combinatorial libraries obtained through libraries from libraries, which is a DOS approach. Using MACCS keys, radial and different pharmacophoric fingerprints as well as six molecular properties, it was demonstrated the increased structural and property diversity of the libraries from libraries over the individual libraries. Comparison of the libraries to existing drugs, NCI Diversity and the Molecular Libraries Small Molecule Repository revealed the structural uniqueness of the combinatorial libraries (mean similarity < 0.5 for any fingerprint representation). In particular, bis-cyclic thiourea libraries were the most structurally dissimilar to drugs retaining drug-like character in property space. This study represents the first comprehensive quantification of the diversity of libraries from libraries providing a solid quantitative approach to compare and contrast the diversity of DOS libraries with existing drugs or any other compound collection. PMID:21294850

  4. Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries.

    PubMed

    López-Vallejo, Fabian; Nefzi, Adel; Bender, Andreas; Owen, John R; Nabney, Ian T; Houghten, Richard A; Medina-Franco, José L

    2011-05-01

    Combinatorial libraries continue to play a key role in drug discovery. To increase structural diversity, several experimental methods have been developed. However, limited efforts have been performed so far to quantify the diversity of the broadly used diversity-oriented synthetic libraries. Herein, we report a comprehensive characterization of 15 bis-diazacyclic combinatorial libraries obtained through libraries from libraries, which is a diversity-oriented synthetic approach. Using MACCS keys, radial and different pharmacophoric fingerprints as well as six molecular properties, it was demonstrated the increased structural and property diversity of the libraries from libraries over the individual libraries. Comparison of the libraries to existing drugs, NCI diversity, and the Molecular Libraries Small Molecule Repository revealed the structural uniqueness of the combinatorial libraries (mean similarity <0.5 for any fingerprint representation). In particular, bis-cyclic thiourea libraries were the most structurally dissimilar to drugs retaining drug-like character in property space. This study represents the first comprehensive quantification of the diversity of libraries from libraries providing a solid quantitative approach to compare and contrast the diversity of diversity-oriented synthetic libraries with existing drugs or any other compound collection. © 2011 John Wiley & Sons A/S.

  5. Mass Spectral Library Quality Assurance by Inter-Library Comparison

    NASA Astrophysics Data System (ADS)

    Wallace, William E.; Ji, Weihua; Tchekhovskoi, Dmitrii V.; Phinney, Karen W.; Stein, Stephen E.

    2017-01-01

    A method to discover and correct errors in mass spectral libraries is described. Comparing across a set of highly curated reference libraries compounds that have the same chemical structure quickly identifies entries that are outliers. In cases where three or more entries for the same compound are compared, the outlier as determined by visual inspection was almost always found to contain the error. These errors were either in the spectrum itself or in the chemical descriptors that accompanied it. The method is demonstrated on finding errors in compounds of forensic interest in the NIST/EPA/NIH Mass Spectral Library. The target list of compounds checked was the Scientific Working Group for the Analysis of Seized Drugs (SWGDRUG) mass spectral library. Some examples of errors found are described. A checklist of errors that curators should look for when performing inter-library comparisons is provided.

  6. Mass Spectral Library Quality Assurance by Inter-Library Comparison

    NASA Astrophysics Data System (ADS)

    Wallace, William E.; Ji, Weihua; Tchekhovskoi, Dmitrii V.; Phinney, Karen W.; Stein, Stephen E.

    2017-04-01

    A method to discover and correct errors in mass spectral libraries is described. Comparing across a set of highly curated reference libraries compounds that have the same chemical structure quickly identifies entries that are outliers. In cases where three or more entries for the same compound are compared, the outlier as determined by visual inspection was almost always found to contain the error. These errors were either in the spectrum itself or in the chemical descriptors that accompanied it. The method is demonstrated on finding errors in compounds of forensic interest in the NIST/EPA/NIH Mass Spectral Library. The target list of compounds checked was the Scientific Working Group for the Analysis of Seized Drugs (SWGDRUG) mass spectral library. Some examples of errors found are described. A checklist of errors that curators should look for when performing inter-library comparisons is provided.

  7. Mass Spectral Library Quality Assurance by Inter-Library Comparison.

    PubMed

    Wallace, William E; Ji, Weihua; Tchekhovskoi, Dmitrii V; Phinney, Karen W; Stein, Stephen E

    2017-01-26

    A method to discover and correct errors in mass spectral libraries is described. Comparing across a set of highly curated reference libraries compounds that have the same chemical structure quickly identifies entries that are outliers. In cases where three or more entries for the same compound are compared, the outlier as determined by visual inspection was almost always found to contain the error. These errors were either in the spectrum itself or in the chemical descriptors that accompanied it. The method is demonstrated on finding errors in compounds of forensic interest in the NIST/EPA/NIH Mass Spectral Library. The target list of compounds checked was the Scientific Working Group for the Analysis of Seized Drugs (SWGDRUG) mass spectral library. Some examples of errors found are described. A checklist of errors that curators should look for when performing inter-library comparisons is provided. Graphical Abstract ᅟ.

  8. Identification of cancer specific ligands from one-bead one compound combinatorial libraries to develop theranostics agents against oral squamous cell carcinoma

    NASA Astrophysics Data System (ADS)

    Yang, Frances Fan

    Background: Oral squamous cell carcinoma (OSCC) is one of the most prevalent disease worldwide. One-bead one-compound (OBOC) combinatorial technology is a powerful method to identify peptidomimetic ligands against a variety of receptors on cell surfaces. We therefore hypothesized that cancer specific ligands against OSCC might be identified and can be conjugated to optical dyes or nanocarriers to develop theranostic agents against OSCC. Material and methods: Different OSCC cell lines were incubated with OBOC libraries and beads with cell binding were sorted and then screened with normal human cells to identify peptide-beads binding to different OSCC cell lines but not binding to normal human cells. The molecular probes of OSCC were developed by biotinylating the carboxyl end of the ligands. OSCC theranostic agents were developed by decorating LLY13 with NPs and evaluated by using orthotopic bioluminescent oral cancer model. Results: Six OSCC specific ligands were discovered. Initial peptide-histochemistry study indicated that LLY12 and LLY13 were able to specifically detect OSCC cells grown on chamber slides at the concentration of 1 muM. In addition, LLY13 was found to penetrate into the OSCC cells and accumulate in the cytoplasm, and nucleus. After screened with a panel of integrin antibodies, only anti-alpha3 antibody was able to block most of OSCC cells binding to the LLY13 beads. OSCC theranostic agents developed using targeting LLY13 micelles (25+/- 4nm in diameter) were more efficient in binding to HSC-3 cancer cells compared to non-targeting micelles. Ex vivo images demonstrated that xenografts from the mice with targeting micelles appeared to have higher signals than the non-targeting groups. Conclusion: LLY13 has promising in vitro and in vivo targeting activity against OSCC. In addition, LLY13 is also able to penetrate into cancer cells via endocytosis. Initial study indicated that alpha3 integrin might partially be the corresponding receptor involved

  9. In Vivo Evaluation of 11C-labeled Three Radioligands for Glycine Transporter 1 in the Mouse Brain

    PubMed Central

    Zhang, Ji-chun; Toyohara, Jun; Wu, Jin; Ishiwata, Kiichi

    2012-01-01

    Objective Glycine transporter 1 (GlyT-1) is one of the most attractive therapeutic targets for schizophrenia. There is great interest in developing radioligands for in vivo imaging of GlyT-1 in the brain using positron emission tomography. Here, we report the properties of three novel non-sarcosine-based radioligands [11C]CHIBA-3007, [11C]CHIBA-3009, and [11C]CHIBA-3011, for GlyT-1 imaging in the mouse brain in vivo. Methods The three radioligands were synthesized by N-[11C] methylation of the corresponding desmethyl precursor. A pharmacological characterization of these radioligands for in vivo imaging of GlyT-1 in the brain was conducted using male ddY mice. Results [11C]CHIBA-3009 and [11C]CHIBA-3011 were scarcely incorporated into the brain, whereas [11C]CHIBA-3007 showed slight but considerable brain uptake. Regional brain uptake of [11C]CHIBA-3007 (medulla oblongata>cerebellum>cortex) was similar to the distribution of the GlyT-1 protein. However, pretreatment with CHIBA-3007 (1 mg/kg) or the GlyT-1 selective inhibitor ALX5407 (N-[(3R)-3-([1,1'-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine) (30 mg/kg) did not significantly decrease brain uptake of [11C]CHIBA-3007, suggesting low specific binding to GlyT-1. Pretreatment with cyclosporin A significantly increased brain uptake of [11C]CHIBA-3009 and [11C]CHIBA-3011, suggesting a role for P-glycoprotein in the brain uptake of these ligands. All three radioligands were rapidly degraded intact forms were 3-18% in plasma and 15-74% in the brain at 15 min after injection. Conclusion The results suggest that these three radioligands are not suitable for in vivo imaging of GlyT-1 in the brain because of low brain uptake and rapid metabolism. Further structural refinement is necessary to enhance brain uptake. PMID:23429671

  10. A two-channel detection method for autofluorescence correction and efficient on-bead screening of one-bead one-compound combinatorial libraries using the COPAS fluorescence activated bead sorting system

    NASA Astrophysics Data System (ADS)

    Hintersteiner, Martin; Auer, Manfred

    2013-03-01

    One-bead one-compound combinatorial library beads exhibit varying levels of autofluorescence after solid phase combinatorial synthesis. Very often this causes significant problems for automated on-bead screening using TentaGel beads and fluorescently labeled target proteins. Herein, we present a method to overcome this limitation when fluorescence activated bead sorting is used as the screening method. We have equipped the COPAS bead sorting instrument with a high-speed profiling unit and developed a spectral autofluorescence correction method. The correction method is based on a simple algebraic operation using the fluorescence data from two detection channels and is applied on-the-fly in order to reliably identify hit beads by COPAS bead sorting. Our method provides a practical tool for the fast and efficient isolation of hit beads from one-bead one-compound library screens using either fluorescently labeled target proteins or biotinylated target proteins. This method makes hit bead identification easier and more reliable. It reduces false positives and eliminates the need for time-consuming pre-sorting of library beads in order to remove autofluorescent beads.

  11. Library 2000.

    ERIC Educational Resources Information Center

    Drake, Miriam A.

    In fall 1984, the Georgia Institute of Technology administration and library staff began planning for Library 2000, a project aimed at creating a showcase library to demonstrate the application of the latest information technology in an academic and research environment. The purposes of Library 2000 include: increasing awareness of students,…

  12. Library Buildings.

    ERIC Educational Resources Information Center

    Manley, Will; And Others

    1989-01-01

    The innovative designs of three libraries are described: the Tempe (Arizona) Public Library, which emphasizes services for children and students; an underground library at Park College, Missouri; and a public library located in the Vancouver (Washington) Mall. The fourth article describes the work going on to restore the Los Angeles (California)…

  13. Library Computing.

    ERIC Educational Resources Information Center

    Dayall, Susan A.; And Others

    1987-01-01

    Six articles on computers in libraries discuss training librarians and staff to use new software; appropriate technology; system upgrades of the Research Libraries Group's information system; pre-IBM PC microcomputers; multiuser systems for small to medium-sized libraries; and a library user's view of the traditional card catalog. (EM)

  14. Special Libraries.

    ERIC Educational Resources Information Center

    Foskett, D. J.

    The Special Library is distinguished from other libraries as being a library serving a particular group of readers, who have an existence as a group outside of their readership of the library, and whose members direct at least some of their activities towards a common purpose. Thus, the special librarian's first and major responsibility is to know…

  15. Special Libraries

    ERIC Educational Resources Information Center

    Lavendel, Giuliana

    1977-01-01

    Discusses problems involved in maintaining special scientific or engineering libraries, including budget problems, remote storage locations, rental computer retrieval systems, protecting trade secrets, and establishing a magnetic tape library. (MLH)

  16. Library Buildings

    ERIC Educational Resources Information Center

    Allen, Walter C.

    1976-01-01

    Examines a century of library architecture in relation to the changing perceptions of library functions, the development of building techniques and materials, fluctuating esthetic fashions and sometimes wildly erratic economic climates. (Author)

  17. Library fingerprints: a novel approach to the screening of virtual libraries.

    PubMed

    Klon, Anthony E; Diller, David J

    2007-01-01

    We propose a novel method to prioritize libraries for combinatorial synthesis and high-throughput screening that assesses the viability of a particular library on the basis of the aggregate physical-chemical properties of the compounds using a naïve Bayesian classifier. This approach prioritizes collections of related compounds according to the aggregate values of their physical-chemical parameters in contrast to single-compound screening. The method is also shown to be useful in screening existing noncombinatorial libraries when the compounds in these libraries have been previously clustered according to their molecular graphs. We show that the method used here is comparable or superior to the single-compound virtual screening of combinatorial libraries and noncombinatorial libraries and is superior to the pairwise Tanimoto similarity searching of a collection of combinatorial libraries.

  18. Compound Library Screening Identified Cardiac Glycoside Digitoxin as an Effective Growth Inhibitor of Gefitinib-Resistant Non-Small Cell Lung Cancer via Downregulation of α-Tubulin and Inhibition of Microtubule Formation.

    PubMed

    Zhang, Yi-Ze; Chen, Xi; Fan, Xing-Xing; He, Jian-Xing; Huang, Jun; Xiao, Da-Kai; Zhou, Yan-Ling; Zheng, Sen-You; Xu, Jia-Hui; Yao, Xiao-Jun; Liu, Liang; Leung, Elaine Lai-Han

    2016-03-18

    Non-small-cell lung cancer (NSCLC) dominates over 85% of all lung cancer cases. Epidermal growth factor receptor (EGFR) activating mutation is a common situation in NSCLC. In the clinic, molecular-targeting with Gefitinib as a tyrosine kinase inhibitor (TKI) for EGFR downstream signaling is initially effective. However, drug resistance frequently happens due to additional mutation on EGFR, such as substitution from threonine to methionine at amino acid position 790 (T790M). In this study, we screened a traditional Chinese medicine (TCM) compound library consisting of 800 single compounds in TKI-resistance NSCLC H1975 cells, which contains substitutions from leucine to arginine at amino acid 858 (L858R) and T790M mutation on EGFR. Attractively, among these compounds there are 24 compounds CC50 of which was less than 2.5 μM were identified. We have further investigated the mechanism of the most effective one, Digitoxin. It showed a significantly cytotoxic effect in H1975 cells by causing G2 phase arrest, also remarkably activated 5' adenosine monophosphate-activated protein kinase (AMPK). Moreover, we first proved that Digitoxin suppressed microtubule formation through decreasing α-tubulin. Therefore, it confirmed that Digitoxin effectively depressed the growth of TKI-resistance NSCLC H1975 cells by inhibiting microtubule polymerization and inducing cell cycle arrest.

  19. Library Skills.

    ERIC Educational Resources Information Center

    Paul, Karin; Kuhlthau, Carol C.; Branch, Jennifer L.; Solowan, Diane Galloway; Case, Roland; Abilock, Debbie; Eisenberg, Michael B.; Koechlin, Carol; Zwaan, Sandi; Hughes, Sandra; Low, Ann; Litch, Margaret; Lowry, Cindy; Irvine, Linda; Stimson, Margaret; Schlarb, Irene; Wilson, Janet; Warriner, Emily; Parsons, Les; Luongo-Orlando, Katherine; Hamilton, Donald

    2003-01-01

    Includes 19 articles that address issues related to library skills and Canadian school libraries. Topics include information literacy; inquiry learning; critical thinking and electronic research; collaborative inquiry; information skills and the Big 6 approach to problem solving; student use of online databases; library skills; Internet accuracy;…

  20. Library Skills.

    ERIC Educational Resources Information Center

    Paul, Karin; Kuhlthau, Carol C.; Branch, Jennifer L.; Solowan, Diane Galloway; Case, Roland; Abilock, Debbie; Eisenberg, Michael B.; Koechlin, Carol; Zwaan, Sandi; Hughes, Sandra; Low, Ann; Litch, Margaret; Lowry, Cindy; Irvine, Linda; Stimson, Margaret; Schlarb, Irene; Wilson, Janet; Warriner, Emily; Parsons, Les; Luongo-Orlando, Katherine; Hamilton, Donald

    2003-01-01

    Includes 19 articles that address issues related to library skills and Canadian school libraries. Topics include information literacy; inquiry learning; critical thinking and electronic research; collaborative inquiry; information skills and the Big 6 approach to problem solving; student use of online databases; library skills; Internet accuracy;…

  1. Library Computing.

    ERIC Educational Resources Information Center

    Goodgion, Laurel; And Others

    1986-01-01

    Eight articles in special supplement to "Library Journal" and "School Library Journal" cover a computer program called "Byte into Books"; microcomputers and the small library; creating databases with students; online searching with a microcomputer; quality automation software; Meckler Publishing Company's…

  2. Library Computing

    ERIC Educational Resources Information Center

    Library Computing, 1985

    1985-01-01

    Special supplement to "Library Journal" and "School Library Journal" covers topics of interest to school, public, academic, and special libraries planning for automation: microcomputer use, readings in automation, online searching, databases of microcomputer software, public access to microcomputers, circulation, creating a…

  3. Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine β-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer.

    PubMed

    Druzhyna, Nadiya; Szczesny, Bartosz; Olah, Gabor; Módis, Katalin; Asimakopoulou, Antonia; Pavlidou, Athanasia; Szoleczky, Petra; Gerö, Domokos; Yanagi, Kazunori; Törö, Gabor; López-García, Isabel; Myrianthopoulos, Vassilios; Mikros, Emmanuel; Zatarain, John R; Chao, Celia; Papapetropoulos, Andreas; Hellmich, Mark R; Szabo, Csaba

    2016-11-01

    Cystathionine-β-synthase (CBS) has been recently identified as a drug target for several forms of cancer. Currently no potent and selective CBS inhibitors are available. Using a composite collection of 8871 clinically used drugs and well-annotated pharmacological compounds (including the LOPAC library, the FDA Approved Drug Library, the NIH Clinical Collection, the New Prestwick Chemical Library, the US Drug Collection, the International Drug Collection, the 'Killer Plates' collection and a small custom collection of PLP-dependent enzyme inhibitors), we conducted an in vitro screen in order to identify inhibitors for CBS using a primary 7-azido-4-methylcoumarin (AzMc) screen to detect CBS-derived hydrogen sulfide (H2S) production. Initial hits were subjected to counterscreens using the methylene blue assay (a secondary assay to measure H2S production) and were assessed for their ability to quench the H2S signal produced by the H2S donor compound GYY4137. Four compounds, hexachlorophene, tannic acid, aurintricarboxylic acid and benserazide showed concentration-dependent CBS inhibitory actions without scavenging H2S released from GYY4137, identifying them as direct CBS inhibitors. Hexachlorophene (IC50: ∼60μM), tannic acid (IC50: ∼40μM) and benserazide (IC50: ∼30μM) were less potent CBS inhibitors than the two reference compounds AOAA (IC50: ∼3μM) and NSC67078 (IC50: ∼1μM), while aurintricarboxylic acid (IC50: ∼3μM) was equipotent with AOAA. The second reference compound NSC67078 not only inhibited the CBS-induced AzMC fluorescence signal (IC50: ∼1μM), but also inhibited with the GYY4137-induced AzMC fluorescence signal with (IC50 of ∼6μM) indicative of scavenging/non-specific effects. Hexachlorophene (IC50: ∼6μM), tannic acid (IC50: ∼20μM), benserazide (IC50: ∼20μM), and NSC67078 (IC50: ∼0.3μM) inhibited HCT116 colon cancer cells proliferation with greater potency than AOAA (IC50: ∼300μM). In contrast, although a CBS inhibitor

  4. Active compounds from a diverse library of triazolothiadiazole and triazolothiadiazine scaffolds: synthesis, crystal structure determination, cytotoxicity, cholinesterase inhibitory activity, and binding mode analysis.

    PubMed

    Khan, Imtiaz; Ibrar, Aliya; Zaib, Sumera; Ahmad, Sarfraz; Furtmann, Norbert; Hameed, Shahid; Simpson, Jim; Bajorath, Jürgen; Iqbal, Jamshed

    2014-11-01

    In an effort to identify novel cholinesterase candidates for the treatment of Alzheimer's disease (AD), a diverse array of potentially bioactive compounds including triazolothiadiazoles (4a-h and 5a-f) and triazolothiadiazines (6a-h) was obtained in good yields through the cyclocondensation reaction of 4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol (3) with various substituted aryl/heteroaryl/aryloxy acids and phenacyl bromides, respectively. The structures of newly prepared compounds were confirmed by IR, (1)H and (13)C NMR spectroscopy and, in case of 4a, by single crystal X-ray diffraction analysis. The purity of the synthesized compounds was ascertained by elemental analysis. The newly synthesized conjugated heterocycles were screened for cholinesterase inhibitory activity against electric eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE). Among the evaluated hybrids, several compounds were identified as potent inhibitors. Compounds 5b and 5d were most active with an IC50 value of 3.09 ± 0.154 and 11.3 ± 0.267 μM, respectively, against acetylcholinesterase, whereas 5b, 6a and 6g were most potent against butyrylcholinesterase, with an IC50 of 0.585 ± 0.154, 0.781 ± 0.213, and 1.09 ± 0.156 μM, respectively, compared to neostigmine and donepezil as standard drugs. The synthesized heteroaromatic compounds were also tested for their cytotoxic potential against lung carcinoma (H157) and vero cell lines. Among them, compound 6h exhibited highest antiproliferative activity against H157 cell lines, with IC50 value of 0.96 ± 0.43 μM at 1mM concentration as compared to vincristine (IC50=1.03 ± 0.04 μM), standard drug used in this study. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Fast and Facile Synthesis of 4-Nitrophenyl 2-Azidoethylcarbamate Derivatives from N-Fmoc-Protected α-Amino Acids as Activated Building Blocks for Urea Moiety-Containing Compound Library.

    PubMed

    Chen, Ying-Ying; Chang, Li-Te; Chen, Hung-Wei; Yang, Chia-Ying; Hsin, Ling-Wei

    2017-03-13

    A fast and facile synthesis of a series of 4-nitrophenyl 2-azidoethylcarbamate derivatives as activated urea building blocks was developed. The N-Fmoc-protected 2-aminoethyl mesylates derived from various commercially available N-Fmoc-protected α-amino acids, including those having functionalized side chains with acid-labile protective groups, were directly transformed into 4-nitrophenyl 2-azidoethylcarbamate derivatives in 1 h via a one-pot two-step reaction. These urea building blocks were utilized for the preparation of a series of urea moiety-containing mitoxantrone-amino acid conjugates in 75-92% yields and parallel solution-phase synthesis of a urea compound library consisted of 30 members in 38-70% total yields.

  6. Libraries program

    USGS Publications Warehouse

    2011-01-01

    The U.S. Congress authorized a library for the U.S. Geological Survey (USGS) in 1879. The library was formally established in 1882 with the naming of the first librarian and began with a staff of three and a collection of 1,400 books. Today, the USGS Libraries Program is one of the world's largest Earth and natural science repositories and a resource of national significance used by researchers and the public worldwide.

  7. America's Star Libraries: Top-Rated Libraries

    ERIC Educational Resources Information Center

    Lance, Keith Curry; Lyons, Ray

    2009-01-01

    "Library Journal"'s national rating of public libraries, the "LJ" Index of Public Library Service 2009, Round 2, identifies 258 "star" libraries. Created by Keith Curry Lance and Ray Lyons and based on 2007 data from the IMLS, it rates 7,268 public libraries. The top libraries in each group get five, four, or three stars. All included libraries,…

  8. America's Star Libraries: Top-Rated Libraries

    ERIC Educational Resources Information Center

    Lance, Keith Curry; Lyons, Ray

    2009-01-01

    "Library Journal"'s national rating of public libraries, the "LJ" Index of Public Library Service 2009, Round 2, identifies 258 "star" libraries. Created by Keith Curry Lance and Ray Lyons and based on 2007 data from the IMLS, it rates 7,268 public libraries. The top libraries in each group get five, four, or three stars. All included libraries,…

  9. Library Research.

    ERIC Educational Resources Information Center

    Wright, Nancy Kirkpatrick

    This workbook, designed for a Library Research course at Yavapai College, provides 15 lessons in advanced library reference skills. Each lesson provides explanatory text and reinforcement exercises. After Lesson I introduces specialized dictionaries and encyclopedias (e.g., for foreign languages, medicine, music, economics, social sciences, and…

  10. Privatizing Libraries

    ERIC Educational Resources Information Center

    Jerrard, Jane; Bolt, Nancy; Strege, Karen

    2012-01-01

    This timely special report from ALA Editions provides a succinct but comprehensive overview of the "privatization" of public libraries. It provides a history of the trend of local and state governments privatizing public services and assets, and then examines the history of public library privatization right up to the California…

  11. Library Research.

    ERIC Educational Resources Information Center

    Wright, Nancy Kirkpatrick

    This workbook, designed for a Library Research course at Yavapai College, provides 15 lessons in advanced library reference skills. Each lesson provides explanatory text and reinforcement exercises. After Lesson I introduces specialized dictionaries and encyclopedias (e.g., for foreign languages, medicine, music, economics, social sciences, and…

  12. Privatizing Libraries

    ERIC Educational Resources Information Center

    Jerrard, Jane; Bolt, Nancy; Strege, Karen

    2012-01-01

    This timely special report from ALA Editions provides a succinct but comprehensive overview of the "privatization" of public libraries. It provides a history of the trend of local and state governments privatizing public services and assets, and then examines the history of public library privatization right up to the California…

  13. An Epigenetic Compound Library Screen Identifies BET Inhibitors That Promote HSV-1 and -2 Replication by Bridging P-TEFb to Viral Gene Promoters through BRD4.

    PubMed

    Ren, Ke; Zhang, Wei; Chen, Xiaoqing; Ma, Yingyu; Dai, Yue; Fan, Yimei; Hou, Yayi; Tan, Ren Xiang; Li, Erguang

    2016-10-01

    The human HSV-1 and -2 are common pathogens of human diseases. Both host and viral factors are involved in HSV lytic infection, although detailed mechanisms remain elusive. By screening a chemical library of epigenetic regulation, we identified bromodomain-containing protein 4 (BRD4) as a critical player in HSV infection. We show that treatment with pan BD domain inhibitor enhanced both HSV infection. Using JQ1 as a probe, we found that JQ1, a defined BD1 inhibitor, acts through BRD4 protein since knockdown of BRD4 expression ablated JQ1 effect on HSV infection. BRD4 regulates HSV replication through complex formation involving CDK9 and RNAP II; whereas, JQ1 promotes HSV-1 infection by allocating the complex to HSV gene promoters. Therefore, suppression of BRD4 expression or inhibition of CDK9 activity impeded HSV infection. Our data support a model that JQ1 enhances HSV infection by switching BRD4 to transcription regulation of viral gene expression from chromatin targeting since transient expression of BRD4 BD1 or BD1/2 domain had similar effect to that by JQ1 treatment. In addition to the identification that BRD4 is a modulator for JQ1 action on HSV infection, this study demonstrates BRD4 has an essential role in HSV infection.

  14. An Epigenetic Compound Library Screen Identifies BET Inhibitors That Promote HSV-1 and -2 Replication by Bridging P-TEFb to Viral Gene Promoters through BRD4

    PubMed Central

    Chen, Xiaoqing; Ma, Yingyu; Dai, Yue; Fan, Yimei; Hou, Yayi; Tan, Ren Xiang

    2016-01-01

    The human HSV-1 and -2 are common pathogens of human diseases. Both host and viral factors are involved in HSV lytic infection, although detailed mechanisms remain elusive. By screening a chemical library of epigenetic regulation, we identified bromodomain-containing protein 4 (BRD4) as a critical player in HSV infection. We show that treatment with pan BD domain inhibitor enhanced both HSV infection. Using JQ1 as a probe, we found that JQ1, a defined BD1 inhibitor, acts through BRD4 protein since knockdown of BRD4 expression ablated JQ1 effect on HSV infection. BRD4 regulates HSV replication through complex formation involving CDK9 and RNAP II; whereas, JQ1 promotes HSV-1 infection by allocating the complex to HSV gene promoters. Therefore, suppression of BRD4 expression or inhibition of CDK9 activity impeded HSV infection. Our data support a model that JQ1 enhances HSV infection by switching BRD4 to transcription regulation of viral gene expression from chromatin targeting since transient expression of BRD4 BD1 or BD1/2 domain had similar effect to that by JQ1 treatment. In addition to the identification that BRD4 is a modulator for JQ1 action on HSV infection, this study demonstrates BRD4 has an essential role in HSV infection. PMID:27764245

  15. Quality evaluation of tandem mass spectral libraries.

    PubMed

    Oberacher, Herbert; Weinmann, Wolfgang; Dresen, Sebastian

    2011-06-01

    Tandem mass spectral libraries are gaining more and more importance for the identification of unknowns in different fields of research, including metabolomics, forensics, toxicology, and environmental analysis. Particularly, the recent invention of reliable, robust, and transferable libraries has increased the general acceptance of these tools. Herein, we report on results obtained from thorough evaluation of the match reliabilities of two tandem mass spectral libraries: the MSforID library established by the Oberacher group in Innsbruck and the Weinmann library established by the Weinmann group in Freiburg. Three different experiments were performed: (1) Spectra of the libraries were searched against their corresponding library after excluding either this single compound-specific spectrum or all compound-specific spectra prior to searching; (2) the libraries were searched against each other using either library as reference set or sample set; (3) spectra acquired on different mass spectrometric instruments were matched to both libraries. Almost 13,000 tandem mass spectra were included in this study. The MSforID search algorithm was used for spectral matching. Statistical evaluation of the library search results revealed that principally both libraries enable the sensitive and specific identification of compounds. Due to higher mass accuracy of the QqTOF compared with the QTrap instrument, matches to the MSforID library were more reliable when comparing spectra with both libraries. Furthermore, only the MSforID library was shown to be efficiently transferable to different kinds of tandem mass spectrometers, including "tandem-in-time" instruments; this is due to the coverage of a large range of different collision energy settings-including the very low range-which is an outstanding characteristics of the MSforID library.

  16. Screen of FDA-approved drug library identifies maprotiline, an antibiofilm and antivirulence compound with QseC sensor-kinase dependent activity in Francisella novicida.

    PubMed

    Dean, Scott N; van Hoek, Monique L

    2015-01-01

    Development of new therapeutics against Select Agents such as Francisella is critical preparation in the event of bioterrorism. Testing FDA-approved drugs for this purpose may yield new activities unrelated to their intended purpose and may hasten the discovery of new therapeutics. A library of 420 FDA-approved drugs was screened for antibiofilm activity against a model organism for human tularemia, Francisella (F.) novicida, excluding drugs that significantly inhibited growth. The initial screen was based on the 2-component system (TCS) dependent biofilm effect, thus, the QseC dependence of maprotiline anti-biofilm action was demonstrated. By comparing their FDA-approved uses, chemical structures, and other properties of active drugs, toremifene and polycyclic antidepressants maprotiline and chlorpromazine were identified as being highly active against F. novicida biofilm formation. Further down-selection excluded toremifene for its membrane active activity and chlorpromazine for its high antimicrobial activity. The mode of action of maprotiline against F. novicida was sought. It was demonstrated that maprotiline was able to significantly down-regulate the expression of the virulence factor IglC, encoded on the Francisella Pathogenicity Island (FPI), suggesting that maprotiline is exerting an effect on bacterial virulence. Further studies showed that maprotiline significantly rescued F. novicida infected wax worm larvae. In vivo studies demonstrated that maprotiline treatment could prolong time to disease onset and survival in F. novicida infected mice. These results suggest that an FDA-approved drug such as maprotiline has the potential to combat Francisella infection as an antivirulence agent, and may have utility in combination with antibiotics.

  17. Screen of FDA-approved drug library identifies maprotiline, an antibiofilm and antivirulence compound with QseC sensor-kinase dependent activity in Francisella novicida

    PubMed Central

    Dean, Scott N; van Hoek, Monique L

    2015-01-01

    Development of new therapeutics against Select Agents such as Francisella is critical preparation in the event of bioterrorism. Testing FDA-approved drugs for this purpose may yield new activities unrelated to their intended purpose and may hasten the discovery of new therapeutics. A library of 420 FDA-approved drugs was screened for antibiofilm activity against a model organism for human tularemia, Francisella (F.) novicida, excluding drugs that significantly inhibited growth. The initial screen was based on the 2-component system (TCS) dependent biofilm effect, thus, the QseC dependence of maprotiline anti-biofilm action was demonstrated. By comparing their FDA-approved uses, chemical structures, and other properties of active drugs, toremifene and polycyclic antidepressants maprotiline and chlorpromazine were identified as being highly active against F. novicida biofilm formation. Further down-selection excluded toremifene for its membrane active activity and chlorpromazine for its high antimicrobial activity. The mode of action of maprotiline against F. novicida was sought. It was demonstrated that maprotiline was able to significantly down-regulate the expression of the virulence factor IglC, encoded on the Francisella Pathogenicity Island (FPI), suggesting that maprotiline is exerting an effect on bacterial virulence. Further studies showed that maprotiline significantly rescued F. novicida infected wax worm larvae. In vivo studies demonstrated that maprotiline treatment could prolong time to disease onset and survival in F. novicida infected mice. These results suggest that an FDA-approved drug such as maprotiline has the potential to combat Francisella infection as an antivirulence agent, and may have utility in combination with antibiotics. PMID:26155740

  18. Evaluation of laser diode thermal desorption (LDTD) coupled with tandem mass spectrometry (MS/MS) for support of in vitro drug discovery assays: increasing scope, robustness and throughput of the LDTD technique for use with chemically diverse compound libraries.

    PubMed

    Beattie, Iain; Smith, Aaron; Weston, Daniel J; White, Peter; Szwandt, Simon; Sealey, Laura

    2012-02-05

    Within the drug discovery environment, the key process in optimising the chemistry of a structural series toward a potential drug candidate is the design, make and test cycle, in which the primary screens consist of a number of in vitro assays, including metabolic stability, cytochrome P450 inhibition, and time-dependent inhibition assays. These assays are often carried out using multiple drug compounds with chemically diverse structural features, often in a 96 well-plate format for maximum time-efficiency, and are supported using rapid liquid chromatographic (LC) sample introduction with a tandem mass spectrometry (MS/MS) selected reaction monitoring (SRM) endpoint, taking around 6.5 h per plate. To provide a faster time-to-decision at this critical point, there exists a requirement for higher sample throughput and a robust, well-characterized analytical alternative. This paper presents a detailed evaluation of laser diode thermal desorption (LDTD), a relatively new ambient sample ionization technique, for compound screening assays. By systematic modification of typical LDTD instrumentation and workflow, and providing deeper understanding around overcoming a number of key issues, this work establishes LDTD as a practical, rapid alternative to conventional LC-MS/MS in drug discovery, without need for extensive sample preparation or expensive, scope-limiting internal standards. Analysis of both the five and three cytochrome P450 competitive inhibition assay samples by LDTD gave improved sample throughput (0.75 h per plate) and provided comparable data quality as the IC₅₀ values obtained were within 3 fold of those calculated from the LC-MS/MS data. Additionally when applied generically to a chemically diverse library of over 250 proprietary compounds from the AstraZeneca design, make and test cycle, LDTD demonstrated a success rate of 98%.

  19. Antituberculosis activity of the molecular libraries screening center network library.

    PubMed

    Maddry, Joseph A; Ananthan, Subramaniam; Goldman, Robert C; Hobrath, Judith V; Kwong, Cecil D; Maddox, Clinton; Rasmussen, Lynn; Reynolds, Robert C; Secrist, John A; Sosa, Melinda I; White, E Lucile; Zhang, Wei

    2009-09-01

    There is an urgent need for the discovery and development of new antitubercular agents that target novel biochemical pathways and treat drug-resistant forms of the disease. One approach to addressing this need is through high-throughput screening of drug-like small molecule libraries against the whole bacterium in order to identify a variety of new, active scaffolds that will stimulate additional biological research and drug discovery. Through the Molecular Libraries Screening Center Network, the NIAID Tuberculosis Antimicrobial Acquisition and Coordinating Facility tested a 215,110-compound library against Mycobacterium tuberculosis strain H37Rv. A medicinal chemistry survey of the results from the screening campaign is reported herein.

  20. [The Presidential Libraries.

    ERIC Educational Resources Information Center

    Webb, John

    There are seven Presidential libraries in various states of existence, from quite active to proposed: (1) Franklin D. Roosevelt Library, (2) Harry S. Truman Library, (3) Herbert Hoover Library, (4) Dwight D. Eisenhower Library, (5) John F. Kennedy Memorial Library (6) Lyndon B. Johnson Library and (7) Rutherford B. Hayes Memorial Library. Each…

  1. Academic Libraries

    ERIC Educational Resources Information Center

    Library Journal, 1970

    1970-01-01

    Building data is given for the following academic libraries: (1) Rosary College, River Forest, Illinois; (2) Abilene Christian College, Abilene, Texas; (3) University of California, San Diego, La Jolla, California. (MF)

  2. Digital Libraries.

    ERIC Educational Resources Information Center

    Fox, Edward A.; Urs, Shalini R.

    2002-01-01

    Provides an overview of digital libraries research, practice, and literature. Highlights include new technologies; redefining roles; historical background; trends; creating digital content, including conversion; metadata; organizing digital resources; services; access; information retrieval; searching; natural language processing; visualization;…

  3. Digital Libraries.

    ERIC Educational Resources Information Center

    Fox, Edward A.; Urs, Shalini R.

    2002-01-01

    Provides an overview of digital libraries research, practice, and literature. Highlights include new technologies; redefining roles; historical background; trends; creating digital content, including conversion; metadata; organizing digital resources; services; access; information retrieval; searching; natural language processing; visualization;…

  4. Presidential Libraries

    ERIC Educational Resources Information Center

    Cole, Garold L.

    1972-01-01

    Presented are a description of the history of the presidential papers in the United States, the development and functions of the presidential library system, and a brief look at future developments. (39 references) (Author)

  5. Callpath Library

    SciTech Connect

    Gamblin, T.

    2013-11-09

    The "Callpath Library" is a software abstraction layer over a number of stack tracing utilities. It allows tool develoopers to conveniently represent and mNipulate call paths gathered fro U. Wisconsin's Stackwalker API and GNU Backtrace.

  6. Construction of a natural product library containing secondary metabolites produced by actinomycetes.

    PubMed

    Takagi, Motoki; Shin-Ya, Kazuo

    2012-09-01

    To construct a natural product library for drug screening, we isolated secondary metabolites from a wide variety of actinomycetes cultured from marine sponges. The results suggested that marine sponges are a promising source of actinomycetes with the potential to produce new metabolites. Furthermore, we evaluated the chemical space occupied by our natural product library (CB library) by multidimensional principal component analysis and compared it with a commercially available compound library (ZINC library), which was randomly selected from the ZINC library (approximately 30 000 000 compounds). The CB library occupied a wider chemical space than the ZINC library. Bioactive compounds in the CB library possessed a wide chemical space that was not covered by ZINC library. These results indicate that the CB library mainly comprises secondary metabolites from actinomycetes, and it has great potential as a source of compounds for drug screening.

  7. Chemical Space of DNA-Encoded Libraries.

    PubMed

    Franzini, Raphael M; Randolph, Cassie

    2016-07-28

    In recent years, DNA-encoded chemical libraries (DECLs) have attracted considerable attention as a potential discovery tool in drug development. Screening encoded libraries may offer advantages over conventional hit discovery approaches and has the potential to complement such methods in pharmaceutical research. As a result of the increased application of encoded libraries in drug discovery, a growing number of hit compounds are emerging in scientific literature. In this review we evaluate reported encoded library-derived structures and identify general trends of these compounds in relation to library design parameters. We in particular emphasize the combinatorial nature of these libraries. Generally, the reported molecules demonstrate the ability of this technology to afford hits suitable for further lead development, and on the basis of them, we derive guidelines for DECL design.

  8. America's Star Libraries

    ERIC Educational Resources Information Center

    Lyons, Ray; Lance, Keith Curry

    2009-01-01

    "Library Journal"'s new national rating of public libraries, the "LJ" Index of Public Library Service, identifies 256 "star" libraries. It rates 7,115 public libraries. The top libraries in each group get five, four, or three Michelin guide-like stars. All included libraries, stars or not, can use their scores to learn from their peers and improve…

  9. Personal Virtual Libraries

    ERIC Educational Resources Information Center

    Pappas, Marjorie L.

    2004-01-01

    Virtual libraries are becoming more and more common. Most states have a virtual library. A growing number of public libraries have a virtual presence on the Web. Virtual libraries are a growing addition to school library media collections. The next logical step would be personal virtual libraries. A personal virtual library (PVL) is a collection…

  10. America's Star Libraries

    ERIC Educational Resources Information Center

    Lyons, Ray; Lance, Keith Curry

    2009-01-01

    "Library Journal"'s new national rating of public libraries, the "LJ" Index of Public Library Service, identifies 256 "star" libraries. It rates 7,115 public libraries. The top libraries in each group get five, four, or three Michelin guide-like stars. All included libraries, stars or not, can use their scores to learn from their peers and improve…

  11. Personal Virtual Libraries

    ERIC Educational Resources Information Center

    Pappas, Marjorie L.

    2004-01-01

    Virtual libraries are becoming more and more common. Most states have a virtual library. A growing number of public libraries have a virtual presence on the Web. Virtual libraries are a growing addition to school library media collections. The next logical step would be personal virtual libraries. A personal virtual library (PVL) is a collection…

  12. Automated recycling of chemistry for virtual screening and library design.

    PubMed

    Vainio, Mikko J; Kogej, Thierry; Raubacher, Florian

    2012-07-23

    An early stage drug discovery project needs to identify a number of chemically diverse and attractive compounds. These hit compounds are typically found through high-throughput screening campaigns. The diversity of the chemical libraries used in screening is therefore important. In this study, we describe a virtual high-throughput screening system called Virtual Library. The system automatically "recycles" validated synthetic protocols and available starting materials to generate a large number of virtual compound libraries, and allows for fast searches in the generated libraries using a 2D fingerprint based screening method. Virtual Library links the returned virtual hit compounds back to experimental protocols to quickly assess the synthetic accessibility of the hits. The system can be used as an idea generator for library design to enrich the screening collection and to explore the structure-activity landscape around a specific active compound.

  13. Underground Libraries.

    ERIC Educational Resources Information Center

    Fuhlrott, Rolf

    1986-01-01

    Discussion of underground buildings constructed primarily during last two decades for various reasons (energy conservation, density of environment, preservation of landscape and historic buildings) notes advantages, disadvantages, and psychological and design considerations. Examples of underground libraries, built mainly in United States, are…

  14. Public Libraries

    ERIC Educational Resources Information Center

    Library Journal, 1972

    1972-01-01

    Building data is given for the following public libraries: New York, New York; Blue Island, Illinois; Corte Madera, California; Muskogee, Oklahoma: Charlotte, North Carolina; Washington, D.C.; Houston, Texas; Albermarle, North Carolina; Spokane, Washington; and Hemet, California. (Author/NH)

  15. Minnesota Zoological Garden Library.

    ERIC Educational Resources Information Center

    Norell, Angela

    1988-01-01

    Describes the history and functions of the Minnesota Zoological Garden library. Topics covered include the library collections; library services, including online search capabilities; and the various groups of users served by the library. (three references) (CLB)

  16. Symposium on Presidential Libraries.

    ERIC Educational Resources Information Center

    Relyea, Harold C.; And Others

    1994-01-01

    Includes five articles that discuss presidential libraries. Highlights include an overview of the development of the federal presidential library system; the Ronald Reagan library; the Richard Nixon library archives; access at the Gerald Ford library; and computerizing the Jimmy Carter library. (LRW)

  17. Turkish Libraries: Historical Context.

    ERIC Educational Resources Information Center

    Cakin, Irfan

    1984-01-01

    Summary of the development of libraries in Turkey highlights the existence of libraries in the ninth century, the Shamssaddin Altunaba Medrese library in Konya, libraries established during the Ottoman era, reports to reform libraries (1869-70, 1909), and reports and library developments attributed to the Republican Era beginning in 1923. (EJS)

  18. The Sister Libraries Programs.

    ERIC Educational Resources Information Center

    Sager, Don

    2000-01-01

    These articles describe the Sister Libraries program, part of the White House Millennium project, sponsored by the National Commission on Libraries and Information Science and the American Library Association to build relationships with libraries in other cultures. Discusses projects with public and school libraries and library development in…

  19. Turkish Libraries: Historical Context.

    ERIC Educational Resources Information Center

    Cakin, Irfan

    1984-01-01

    Summary of the development of libraries in Turkey highlights the existence of libraries in the ninth century, the Shamssaddin Altunaba Medrese library in Konya, libraries established during the Ottoman era, reports to reform libraries (1869-70, 1909), and reports and library developments attributed to the Republican Era beginning in 1923. (EJS)

  20. Library Research and Statistics.

    ERIC Educational Resources Information Center

    Lynch, Mary Jo; St. Lifer, Evan; Halstead, Kent; Fox, Bette-Lee; Miller, Marilyn L.; Shontz, Marilyn L.

    2001-01-01

    These nine articles discuss research and statistics on libraries and librarianship, including libraries in the United States, Canada, and Mexico; acquisition expenditures in public, academic, special, and government libraries; price indexes; state rankings of public library data; library buildings; expenditures in school library media centers; and…

  1. Twenty-five Years of DNA-Encoded Chemical Libraries.

    PubMed

    Neri, Dario

    2017-05-04

    Reference library: The availability of DNA-encoded chemical libraries containing billions of compounds facilitates the discovery of binding molecules for pharmaceutical applications and for investigating biological processes. This Special Issue highlights the use of this library technology and some of the latest developments in the field. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Strengthening State Library Administrative Agency (Territorial Library).

    ERIC Educational Resources Information Center

    Nieves M. Flores Memorial Library, Agana, Guam.

    This document describes the Basic State Plan Amendments for the Library Services and Construction Act in Guam and the regulations promulgated thereunder. The major projects described under the plan are: Strengthening State Library Administrative Agency; Staff Development; Library Collections, Extention Services, Institutional Libraries; and…

  3. Art Libraries Section. Special Libraries Division. Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    Papers on art libraries, librarianship, and documentation presented at the 1982 International Federation of Library Associations (IFLA) conference include: (1) "The Tyranny of Distance: Art Libraries in Canada," a description by Mary F. Williamson of Canada's regional art libraries which serve both art students and the general public;…

  4. Similarity based virtual screening: a tool for targeted library design.

    PubMed

    Alvesalo, Joni K O; Siiskonen, Antti; Vainio, Mikko J; Tammela, Päivi S M; Vuorela, Pia M

    2006-04-06

    High throughput screening drug discovery utilizes large and expensive compound libraries. As an alternative, a smaller targeted library can be constructed with the aid of the 3D structure of the target molecule. We used the X-ray crystal structure of a protein homologous to the selected target in creation of a small focused library and evaluated inhibition potential of this library against Chlamydia pneumoniae, a common pathogen recently linked to atherosclerosis and risk of myocardial infarction.

  5. Hole filling and library optimization: application to commercially available fragment libraries.

    PubMed

    An, Yuling; Sherman, Woody; Dixon, Steven L

    2012-09-15

    Compound libraries comprise an integral component of drug discovery in the pharmaceutical and biotechnology industries. While in-house libraries often contain millions of molecules, this number pales in comparison to the accessible space of drug-like molecules. Therefore, care must be taken when adding new compounds to an existing library in order to ensure that unexplored regions in the chemical space are filled efficiently while not needlessly increasing the library size. In this work, we present an automated method to fill holes in an existing library using compounds from an external source and apply it to commercially available fragment libraries. The method, called Canvas HF, uses distances computed from 2D chemical fingerprints and selects compounds that fill vacuous regions while not suffering from the problem of selecting only compounds at the edge of the chemical space. We show that the method is robust with respect to different databases and the number of requested compounds to retrieve. We also present an extension of the method where chemical properties can be considered simultaneously with the selection process to bias the compounds toward a desired property space without imposing hard property cutoffs. We compare the results of Canvas HF to those obtained with a standard sphere exclusion method and with random compound selection and find that Canvas HF performs favorably. Overall, the method presented here offers an efficient and effective hole-filling strategy to augment compound libraries with compounds from external sources. The method does not have any fit parameters and therefore it should be applicable in most hole-filling applications.

  6. Graph Library

    SciTech Connect

    Schulz, Martin; Arnold, Dorian

    2007-06-12

    GraphLib is a support library used by other tools to create, manipulate, store, and export graphs. It provides a simple interface to specifS’ arbitrary directed and undirected graphs by adding nodes and edges. Each node and edge can be associated with a set of attributes describing size, color, and shape. Once created, graphs can be manipulated using a set of graph analysis algorithms, including merge, prune, and path coloring operations. GraphLib also has the ability to export graphs into various open formats such as DOT and GML.

  7. Cell Libraries

    NASA Technical Reports Server (NTRS)

    1994-01-01

    A NASA contract led to the development of faster and more energy efficient semiconductor materials for digital integrated circuits. Gallium arsenide (GaAs) conducts electrons 4-6 times faster than silicon and uses less power at frequencies above 100-150 megahertz. However, the material is expensive, brittle, fragile and has lacked computer automated engineering tools to solve this problem. Systems & Processes Engineering Corporation (SPEC) developed a series of GaAs cell libraries for cell layout, design rule checking, logic synthesis, placement and routing, simulation and chip assembly. The system is marketed by Compare Design Automation.

  8. Antituberculosis Activity of the Molecular Libraries Screening Center Network Library

    PubMed Central

    MADDRY, JOSEPH A.; ANANTHAN, SUBRAMANIAM; GOLDMAN, ROBERT C.; HOBRATH, JUDITH V.; KWONG, CECIL D.; MADDOX, CLINTON; RASMUSSEN, LYNN; REYNOLDS, ROBERT C.; SECRIST, JOHN A.; SOSA, MELINDA I.; WHITE, E. LUCILE; ZHANG, WEI

    2009-01-01

    SUMMARY There is an urgent need for the discovery and development of new antitubercular agents that target novel biochemical pathways and treat drug-resistant forms of the disease. One approach to addressing this need is through high-throughput screening of drug-like small molecule libraries against the whole bacterium in order to identify a variety of new, active scaffolds that will stimulate additional biological research and drug discovery. Through the Molecular Libraries Screening Center Network, the NIAID Tuberculosis Antimicrobial Acquisition and Coordinating Facility tested a 215,110-compound library against M. tuberculosis strain H37Rv. A medicinal chemistry survey of the results from the screening campaign is reported herein. PMID:19783214

  9. 11C-Labeling of Aryl Ketones as Candidate Histamine Subtype-3 Receptor PET Radioligands through Pd(0)-Mediated 11C-Carbonylative Coupling

    PubMed Central

    Siméon, Fabrice G.; Culligan, William J.; Lu, Shuiyu; Pike, Victor W.

    2017-01-01

    Pd(0)-mediated coupling between iodoarenes, [11C]carbon monoxide and aryltributylstannanes has been used to prepare simple model [11C]aryl ketones. Here, we aimed to label four 2-aminoethylbenzofuran chemotype based molecules ([11C]1–4) in the carbonyl position, as prospective positron emission tomography (PET) radioligands for the histamine subtype 3 receptor (H3R) by adapting this methodology with use of aryltrimethylstannanes. Radiosynthesis was successfully performed on a platform equipped with a mini-autoclave and a liquid handling robotic arm, within a lead-shielded hot-cell. Candidate radioligands were readily formulated in saline containing ethanol (10%, v/v) and ascorbic acid (0.5 mg/10 mL). Yields for preclinical use were in the range of 5–9%, decay-corrected from cyclotron-produced [11C]CO2 and molar activities were >115 GBq/μmol at end of synthesis. Radiochemical purities exceeded >97%. PMID:28498336

  10. (11)C-Labeling of Aryl Ketones as Candidate Histamine Subtype-3 Receptor PET Radioligands through Pd(0)-Mediated (11)C-Carbonylative Coupling.

    PubMed

    Siméon, Fabrice G; Culligan, William J; Lu, Shuiyu; Pike, Victor W

    2017-05-12

    Pd(0)-mediated coupling between iodoarenes, [(11)C]carbon monoxide and aryltributylstannanes has been used to prepare simple model [(11)C]aryl ketones. Here, we aimed to label four 2-aminoethylbenzofuran chemotype based molecules ([(11)C]1-4) in the carbonyl position, as prospective positron emission tomography (PET) radioligands for the histamine subtype 3 receptor (H3R) by adapting this methodology with use of aryltrimethylstannanes. Radiosynthesis was successfully performed on a platform equipped with a mini-autoclave and a liquid handling robotic arm, within a lead-shielded hot-cell. Candidate radioligands were readily formulated in saline containing ethanol (10%, v/v) and ascorbic acid (0.5 mg/10 mL). Yields for preclinical use were in the range of 5-9%, decay-corrected from cyclotron-produced [(11)C]CO₂ and molar activities were >115 GBq/µmol at end of synthesis. Radiochemical purities exceeded >97%.

  11. Cu(I)-catalyzed (11)C carboxylation of boronic acid esters: a rapid and convenient entry to (11)C-labeled carboxylic acids, esters, and amides.

    PubMed

    Riss, Patrick J; Lu, Shuiyu; Telu, Sanjay; Aigbirhio, Franklin I; Pike, Victor W

    2012-03-12

    Rapid and direct: the carboxylation of boronic acid esters with (11)CO(2) provides [(11)C]carboxylic acids as a convenient entry into [(11)C]esters and [(11)C]amides. This conversion of boronates is tolerant to diverse functional groups (e.g., halo, nitro, or carbonyl).

  12. A combined accelerator mass spectrometry-positron emission tomography human microdose study with 14C- and 11C-labelled verapamil

    PubMed Central

    Wagner, Claudia C; Simpson, Marie; Zeitlinger, Markus; Bauer, Martin; Karch, Rudolf; Abrahim, Aiman; Feurstein, Thomas; Schütz, Matthias; Kletter, Kurt; Müller, Markus; Lappin, Graham; Langer, Oliver

    2013-01-01

    Background and Objective In microdose studies, the pharmacokinetic (PK) profile of a drug in blood after administration of a dose up to 100 μg is measured with sensitive analytical techniques, such as accelerator mass spectrometry (AMS). As most drugs exert their effect in tissue rather than blood, methodology is needed for extending PK analysis to different tissue compartments. In the present study, we combined, for the first time, AMS analysis with positron emission tomography (PET) in order to determine the PK profile of the model drug verapamil in plasma and brain of humans. In order to assess PK dose-linearity of verapamil, data were acquired and compared after administration of an intravenous (iv) microdose and an iv microdose dosed concomitantly with an oral therapeutic dose. Methods Six healthy male volunteers received an iv microdose (0.05 mg) (period 1) and an iv microdose dosed concomitantly with an oral therapeutic dose (80 mg) of verapamil (period 2) in a randomized, cross-over, two-period study design. The iv dose was a mixture of (R/S)-[14C]verapamil and (R)-[11C]verapamil and the oral dose was unlabelled racemic verapamil. Brain distribution of radioactivity was measured with PET whereas plasma PK of (R)- and (S)-verapamil was determined with AMS. PET data were analyzed by kinetic modeling to estimate the rate constants for transfer of radioactivity across the blood-brain barrier. Results Most PK parameters of (R)- and (S)-verapamil as well as parameters describing exchange of radioactivity between plasma and brain (K1=0.030±0.003 and 0.031±0.005 mL·mL−1·min−1 and k2=0.099±0.006 and 0.095±0.008 min−1 for period 1 and 2, respectively) were not statistically different between the two periods although there was a trend for non-linear kinetics for the (R)-enantiomer. On the other hand, all PK parameters (except for t1/2) differed significantly between the (R)- and (S)-enantiomers for both periods. Cmax, AUC(0-24) and AUC(0-inf) were higher and CL, V and VSS were lower for the (R)- than for the (S)-enantiomer. Conclusion Combining AMS and PET microdosing allows long term PK data along with information on drug tissue distribution to be acquired in the same subjects thus making it a promising approach to maximize data output from a single clinical study. PMID:21142292

  13. Marketing the Virtual Library

    ERIC Educational Resources Information Center

    Fagan, Jody Condit

    2009-01-01

    Far more people are familiar with their local public or college library facility than their library's website and online resources. In fact, according to a recent survey, 96% of Americans said they had visited a library in person, but less than one-third have visited their online library. Since everyone agrees that online library resources are…

  14. Library Handbook for Faculty.

    ERIC Educational Resources Information Center

    Martinez, Angelina, Ed.

    Discussions of library resources, services and related activities as well as library materials selection and acquisition are provided for faculty to facilitate and enhance their use of the library. Included in the library resources section are books, periodicals, microforms, and special collections and archives. Instruction in library use,…

  15. State Virtual Libraries

    ERIC Educational Resources Information Center

    Pappas, Marjorie L.

    2003-01-01

    Virtual library? Electronic library? Digital library? Online information network? These all apply to the growing number of Web-based resource collections managed by consortiums of state library entities. Some, like "INFOhio" and "KYVL" ("Kentucky Virtual Library"), have been available for a few years, but others are just starting. Searching for…

  16. Genealogy and Libraries.

    ERIC Educational Resources Information Center

    Carothers, Diane Foxhill; And Others

    1983-01-01

    Ten articles describe genealogical collections of the National Archives and Library of Congress, state archives programs, academic research libraries, Allen County Public Library (Indiana), Newberry Library, Church of Jesus Christ of Latter-Day Saints genealogical library, and New England Historic Genealogical Society, and approaches to Black…

  17. Library Directions in 1988.

    ERIC Educational Resources Information Center

    DeCandido, GraceAnne A.

    1989-01-01

    Reviews major library issues and events of 1988, including: (1) the Federal Bureau of Investigation's Library Awareness Program; (2) cooperation with USSR libraries; (3) library finance; (4) preservation; and (5) special programing. News about a number of prominent library professionals is included in a sidebar. (MES)

  18. State Virtual Libraries

    ERIC Educational Resources Information Center

    Pappas, Marjorie L.

    2003-01-01

    Virtual library? Electronic library? Digital library? Online information network? These all apply to the growing number of Web-based resource collections managed by consortiums of state library entities. Some, like "INFOhio" and "KYVL" ("Kentucky Virtual Library"), have been available for a few years, but others are just starting. Searching for…

  19. Marketing the Virtual Library

    ERIC Educational Resources Information Center

    Fagan, Jody Condit

    2009-01-01

    Far more people are familiar with their local public or college library facility than their library's website and online resources. In fact, according to a recent survey, 96% of Americans said they had visited a library in person, but less than one-third have visited their online library. Since everyone agrees that online library resources are…

  20. Medical Library Association

    MedlinePlus

    ... Reforms Wed October 4, 2017 The Medical Library Association (MLA) and American Association of Law Libraries (AALL) have recommended changes that ... 05 PM Barbara Epstein, AHIP, FMLA, Medical Library Association President, 2017–2018 Posted on: October 2, 2017 - ...

  1. Medical Library Statistics *

    PubMed Central

    Keenan, Elizabeth L.

    1965-01-01

    Four compilations of medical library statistics have been published to date, namely those by Louise Darling in 1956, by the Medical Library Association in its 1959 Directory, by Harold Bloomquist in 1962, and by the author in 1964. In addition to these sources and to the annual statistics compiled by the Library Services Branch of the U. S. Office of Education, surveys of pharmacy, hospital, and medical society libraries have been completed recently. Standards for medical and special libraries are being considered by the Medical Library Association through its Guidelines Survey and by the Special Libraries Association through its Statistics Coordinating Project and its Standards Survey. To coordinate the collection of medical library statistics and to make the information readily available to the profession, it is suggested that the Medical Library Association support the collection and publication of statistics of representative medical libraries until such time as the Library Services Branch is able to implement fully its program of library statistics. PMID:14271113

  2. Homecoming for Library Symbol.

    ERIC Educational Resources Information Center

    Egan, Bessie

    1987-01-01

    Discusses the significance and development of the library symbol and the history of its acceptance by the American Library Association (ALA) and the Canadian Library Association (CLA). Suggestions are made for its use. (CLB)

  3. Library design-facilitated high-throughput sequencing of synthetic peptide libraries.

    PubMed

    Vinogradov, Alexander Alexandrovich; Gates, Zachary P; Zhang, Chi; Quartararo, Anthony J; Halloran, Kathryn H; Pentelute, Bradley L

    2017-09-11

    A methodology to achieve high-throughput de novo sequencing of synthetic peptide mixtures is reported. The approach leverages shotgun nano-liquid chromatography coupled with tandem mass spectrometry-based de novo sequencing of library mixtures (up to 2000 peptides), as well as automated data analysis protocols to filter away incorrect assignments, noise and synthetic side-products. To increase the confidence in sequencing results, mass spectrometry-friendly library designs were developed, which enabled unambiguous decoding of up to 600 peptide sequences per hour while maintaining greater than 85% sequence identification rate in most cases. The reliability of the reported decoding strategy was additionally confirmed by matching fragmentation spectra for select authentic peptides identified from library sequencing samples. The methods reported here are directly applicable to screening techniques that yield mixtures of active compounds, including particle sorting of one-bead one-compound libraries, and affinity enrichment of synthetic library mixtures performed in solution.

  4. Virtual screening methods as tools for drug lead discovery from large chemical libraries.

    PubMed

    Ma, X H; Zhu, F; Liu, X; Shi, Z; Zhang, J X; Yang, S Y; Wei, Y Q; Chen, Y Z

    2012-01-01

    Virtual screening methods have been developed and explored as useful tools for searching drug lead compounds from chemical libraries, including large libraries that have become publically available. In this review, we discussed the new developments in exploring virtual screening methods for enhanced performance in searching large chemical libraries, their applications in screening libraries of ~ 1 million or more compounds in the last five years, the difficulties in their applications, and the strategies for further improving these methods.

  5. Resources of Texas Libraries.

    ERIC Educational Resources Information Center

    Holley, Edward G.; Hendricks, Donald D.

    This study of library resources was undertaken as a part of a statewide plan for higher education in Texas. The document includes descriptions of library facilities and resources at the University of Texas at Austin, other universities, and public and private junior and senior colleges. The public library network, health science libraries, law…

  6. Prison Libraries Inside Out.

    ERIC Educational Resources Information Center

    Singer, Glen

    2000-01-01

    Discussion of prison libraries provides an inside look at the correctional institution environment, prison security concerns, inmate patrons and library use, library collections and services, librarians and staff, the day-to-day operation of a prison library, and future possibilities and needs. (Author/LRW)

  7. The "Integrated Library System."

    ERIC Educational Resources Information Center

    Dowlin, Kenneth E.

    1985-01-01

    Reviews internal and external dimensions of library environment that must be taken into account by library managers when choosing an integrated library system. The selection, acquisition, and implementation stages of Maggie III--a computerized library system sensitive to the internal and external organizational environment--are described. (MBR)

  8. California: Library Information Technologies.

    ERIC Educational Resources Information Center

    Will, Barbara, Ed.

    1996-01-01

    Describes six information technology projects in California libraries, including Internet access in public libraries; digital library developments at the University of California, Berkeley; the World Wide Web home page for the state library; Pacific Bell's role in statewide connectivity; state government initiatives; and services of the state…

  9. Realizing the Hybrid Library.

    ERIC Educational Resources Information Center

    Pinfield, Stephen; Eaton, Jonathan; Edwards, Catherine; Russell, Rosemary; Wissenburg, Astrid; Wynne, Peter

    1998-01-01

    Outlines five projects currently funded by the United Kingdom's Electronic Libraries Program (eLib): HyLiFe (Hybrid Library of the Future), MALIBU (MAnaging the hybrid Library for the Benefit of Users), HeadLine (Hybrid Electronic Access and Delivery in the Library Networked Environment), ATHENS (authentication scheme), and BUILDER (Birmingham…

  10. Facility Focus: Libraries.

    ERIC Educational Resources Information Center

    College Planning & Management, 2002

    2002-01-01

    Describes the design of the Charles V. Park Library at Central Michigan University and the Martha Rivers and E. Bronson Ingram Library, an addition to the Frederick Ferris Thompson Memorial Library at Vassar College. Discusses the libraries as examples of merging tradition with technology. Includes photographs. (EV)

  11. Libraries, Ebooks, and Competition

    ERIC Educational Resources Information Center

    Hellman, Eric

    2010-01-01

    People keep writing articles about how valuable libraries are, even with ebooks and the Internet. What people are overlooking is that the reason libraries are having such fits dealing with a changing environment is not that libraries are unrecognized as fountains of value, it's that libraries are so valuable that they attract voracious new…

  12. Growing Competition for Libraries.

    ERIC Educational Resources Information Center

    Gibbons, Susan

    2001-01-01

    Describes the Questia subscription-based online academic digital books library. Highlights include weaknesses of the collection; what college students want from a library; importance of marketing; competition for traditional academic libraries that may help improve library services; and the ability of Questia to overcome barriers and…

  13. The New Library Professional

    ERIC Educational Resources Information Center

    Wilder, Stanley

    2007-01-01

    This article discusses what the growing generation gap among library employees mean for academic research libraries and for the profession. Viewed collectively, the members of the under-35 cohort are a harbinger of a new kind of academic library professional, one whose traits bear directly on the ability of libraries to thrive amid the continuing…

  14. Libraries and Learning

    ERIC Educational Resources Information Center

    Rainie, Lee

    2016-01-01

    The majority of Americans think local libraries serve the educational needs of their communities and families pretty well and library users often outpace others in learning activities. But many do not know about key education services libraries provide. This report provides statistics on library usage and presents key education services provided…

  15. AMERICA 2000 Library Partnership.

    ERIC Educational Resources Information Center

    Office of Educational Research and Improvement (ED), Washington, DC.

    The United States Department of Education, the National Endowment for the Humanities, the Library of Congress, the National Commission on Libraries and Information Science, and the National Institute for Literacy have formed the AMERICA 2000 Library Partnership to support libraries in their work toward the six National Education Goals announced by…

  16. Growing Competition for Libraries.

    ERIC Educational Resources Information Center

    Gibbons, Susan

    2001-01-01

    Describes the Questia subscription-based online academic digital books library. Highlights include weaknesses of the collection; what college students want from a library; importance of marketing; competition for traditional academic libraries that may help improve library services; and the ability of Questia to overcome barriers and…

  17. Oregon Public Libraries.

    ERIC Educational Resources Information Center

    Myhre, Martin

    A Survey of Oregon libraries was conducted to supply current background information on libraries. This information was needed for a long range plan to develop libraries in Oregon which is required by Public Law 91-600. In addition, the details about specific libraries are needed to evaluate applications for federal funds and to evaluate the…

  18. Special Library Services.

    ERIC Educational Resources Information Center

    Ensley, Robert F., Ed.

    1975-01-01

    The September 1975 issue of Illinois Libraries focuses on the needs of the developmentally disabled, physically handicapped, and emotionally disturbed. Articles on library services to the blind and physically handicapped cover standards, services of local public libraries, Library of Congress programs, braille books and sound recordings,…

  19. The Visiting Corporate Library.

    ERIC Educational Resources Information Center

    Ball, Melanie

    1998-01-01

    Describes a visiting information consultant program in a corporate library that was developed to provide library services to more clients, increase library visibility, and to provide new and convenient outreach library services and information to users. The initial pilot program is discussed as are observations that were incorporated into the…

  20. College and University Libraries.

    ERIC Educational Resources Information Center

    Shubert, Joseph F., Ed.; Josey, E. J., Ed.

    1986-01-01

    Following an introductory discussion by E. J. Josey that provides a perspective on college and university libraries, the following essays are presented: (1) "Academic Library Planning--Definitions and Early Planning Studies in Academic Libraries" (Stanton F. Biddle); (2) "Academic Libraries and Academic Computing--Rationale for a…

  1. Libraries and Learning

    ERIC Educational Resources Information Center

    Rainie, Lee

    2016-01-01

    The majority of Americans think local libraries serve the educational needs of their communities and families pretty well and library users often outpace others in learning activities. But many do not know about key education services libraries provide. This report provides statistics on library usage and presents key education services provided…

  2. Libraries, Ebooks, and Competition

    ERIC Educational Resources Information Center

    Hellman, Eric

    2010-01-01

    People keep writing articles about how valuable libraries are, even with ebooks and the Internet. What people are overlooking is that the reason libraries are having such fits dealing with a changing environment is not that libraries are unrecognized as fountains of value, it's that libraries are so valuable that they attract voracious new…

  3. Cable Library Survey Results.

    ERIC Educational Resources Information Center

    Public Service Satellite Consortium, Washington, DC.

    This report summarizes a survey of 198 libraries which had been identified as potential cable libraries which assessed: (1) to what extent a national satellite cable library network might already be in technical existence, (2) how many libraries are connected to cooperative cable companies with satellite hardware and excess receiver capacity, and…

  4. Screening of a virtual mirror-image library of natural products.

    PubMed

    Noguchi, Taro; Oishi, Shinya; Honda, Kaori; Kondoh, Yasumitsu; Saito, Tamio; Ohno, Hiroaki; Osada, Hiroyuki; Fujii, Nobutaka

    2016-06-08

    We established a facile access to an unexplored mirror-image library of chiral natural product derivatives using d-protein technology. In this process, two chemical syntheses of mirror-image substances including a target protein and hit compound(s) allow the lead discovery from a virtual mirror-image library without the synthesis of numerous mirror-image compounds.

  5. America's Star Libraries, 2010: Top-Rated Libraries

    ERIC Educational Resources Information Center

    Lyons, Ray; Lance, Keith Curry

    2010-01-01

    The "LJ" Index of Public Library Service 2010, "Library Journal"'s national rating of public libraries, identifies 258 "star" libraries. Created by Ray Lyons and Keith Curry Lance, and based on 2008 data from the IMLS, it rates 7,407 public libraries. The top libraries in each group get five, four, or three stars. All included libraries, stars or…

  6. America's Star Libraries, 2010: Top-Rated Libraries

    ERIC Educational Resources Information Center

    Lyons, Ray; Lance, Keith Curry

    2010-01-01

    The "LJ" Index of Public Library Service 2010, "Library Journal"'s national rating of public libraries, identifies 258 "star" libraries. Created by Ray Lyons and Keith Curry Lance, and based on 2008 data from the IMLS, it rates 7,407 public libraries. The top libraries in each group get five, four, or three stars. All included libraries, stars or…

  7. Validation of chemical compound library screening for transcriptional co-activator with PDZ-binding motif inhibitors using GFP-fused transcriptional co-activator with PDZ-binding motif.

    PubMed

    Nagashima, Shunta; Maruyama, Junichi; Kawano, Shodai; Iwasa, Hiroaki; Nakagawa, Kentaro; Ishigami-Yuasa, Mari; Kagechika, Hiroyuki; Nishina, Hiroshi; Hata, Yutaka

    2016-06-01

    Transcriptional co-activator with PDZ-binding motif (TAZ) plays versatile roles in cell proliferation and differentiation. It is phosphorylated by large tumor suppressor kinases, the core kinases of the tumor-suppressive Hippo pathway. Phosphorylation induces the cytoplasmic accumulation of TAZ and its degradation. In human cancers, the deregulation of the Hippo pathway and gene amplification enhance TAZ activity. TAZ interacts with TEA domain family members (TEAD), and upregulates genes implicated in epithelial-mesenchymal transition. It also confers stemness to cancer cells. Thus, TAZ activation provides cancer cells with malignant properties and worsens the clinical prognosis. Therefore, TAZ attracts attention as a therapeutic target in cancer therapy. We applied 18 606 small chemical compounds to human osteosarcoma U2OS cells expressing GFP-fused TAZ (GFP-TAZ), monitored the subcellular localization of GFP-TAZ, and selected 33 compounds that shifted GFP-TAZ to the cytoplasm. Unexpectedly, only a limited number of compounds suppressed TAZ-mediated enhancement of TEAD-responsive reporter activity. Moreover, the compounds that weakened TEAD reporter activity did not necessarily decrease the unphosphorylated TAZ. In this study, we focused on three compounds that decreased both TEAD reporter activity and unphosphorylated TAZ, and treated several human cancer cells with these compounds. One compound did not show a remarkable effect, whereas the other two compounds compromised the cell viability in certain cancer cells. In conclusion, the GFP-TAZ-based assay can be used as the first screening for compounds that inhibit TAZ and show anticancer properties. To develop anticancer drugs, we need additional assays to select the compounds.

  8. Rapid Discovery of Functional Small Molecule Ligands against Proteomic Targets through Library-Against-Library Screening.

    PubMed

    Wu, Chun-Yi; Wang, Don-Hong; Wang, Xiaobing; Dixon, Seth M; Meng, Liping; Ahadi, Sara; Enter, Daniel H; Chen, Chao-Yu; Kato, Jason; Leon, Leonardo J; Ramirez, Laura M; Maeda, Yoshiko; Reis, Carolina F; Ribeiro, Brianna; Weems, Brittany; Kung, Hsing-Jien; Lam, Kit S

    2016-06-13

    Identifying "druggable" targets and their corresponding therapeutic agents are two fundamental challenges in drug discovery research. The one-bead-one-compound (OBOC) combinatorial library method has been developed to discover peptides or small molecules that bind to a specific target protein or elicit a specific cellular response. The phage display cDNA expression proteome library method has been employed to identify target proteins that interact with specific compounds. Here, we combined these two high-throughput approaches, efficiently interrogated approximately 10(13) possible molecular interactions, and identified 91 small molecule compound beads that interacted strongly with the phage library. Of 19 compounds resynthesized, 4 were cytotoxic against cancer cells; one of these compounds was found to interact with EIF5B and inhibit protein translation. As more binding pairs are confirmed and evaluated, the "library-against-library" screening approach and the resulting small molecule-protein domain interaction database may serve as a valuable tool for basic research and drug development.

  9. Hospital libraries in perspective.

    PubMed Central

    Holst, R

    1991-01-01

    The proliferation of hospital libraries since World War II has created a generation of librarians who take for granted the existence of libraries in hospitals. A literature review for the first half of the twentieth century presents a picture of uncertainty and struggle for identity for the hospital library. Then as now, hospital libraries reflect the institutions within which they operate. A brief history of the development of the American hospital provides a context for describing the various roles that the hospital library has played within its parent institution during the twentieth century. Some personal reflections on working in a hospital library are also presented. PMID:1998812

  10. Summer library reading programs.

    PubMed

    Fiore, Carole D

    2007-01-01

    Virtually all public libraries in the United States provide some type of summer library reading program during the traditional summer vacation period. Summer library reading programs provide opportunities for students of many ages and abilities to practice their reading skills and maintain skills that are developed during the school year. Fiore summarizes some of the research in the field and relates it to library programs and usage by students. Several traditional and innovative programs from U.S. and Canadian libraries are described. She concludes with a call for further research related to summer library reading programs.

  11. USGS Spectral Library Version 7

    USGS Publications Warehouse

    Kokaly, Raymond F.; Clark, Roger N.; Swayze, Gregg A.; Livo, K. Eric; Hoefen, Todd M.; Pearson, Neil C.; Wise, Richard A.; Benzel, William M.; Lowers, Heather A.; Driscoll, Rhonda L.; Klein, Anna J.

    2017-04-10

    We have assembled a library of spectra measured with laboratory, field, and airborne spectrometers. The instruments used cover wavelengths from the ultraviolet to the far infrared (0.2 to 200 microns [μm]). Laboratory samples of specific minerals, plants, chemical compounds, and manmade materials were measured. In many cases, samples were purified, so that unique spectral features of a material can be related to its chemical structure. These spectro-chemical links are important for interpreting remotely sensed data collected in the field or from an aircraft or spacecraft. This library also contains physically constructed as well as mathematically computed mixtures. Four different spectrometer types were used to measure spectra in the library: (1) Beckman™ 5270 covering the spectral range 0.2 to 3 µm, (2) standard, high resolution (hi-res), and high-resolution Next Generation (hi-resNG) models of Analytical Spectral Devices (ASD) field portable spectrometers covering the range from 0.35 to 2.5 µm, (3) Nicolet™ Fourier Transform Infra-Red (FTIR) interferometer spectrometers covering the range from about 1.12 to 216 µm, and (4) the NASA Airborne Visible/Infra-Red Imaging Spectrometer AVIRIS, covering the range 0.37 to 2.5 µm. Measurements of rocks, soils, and natural mixtures of minerals were made in laboratory and field settings. Spectra of plant components and vegetation plots, comprising many plant types and species with varying backgrounds, are also in this library. Measurements by airborne spectrometers are included for forested vegetation plots, in which the trees are too tall for measurement by a field spectrometer. This report describes the instruments used, the organization of materials into chapters, metadata descriptions of spectra and samples, and possible artifacts in the spectral measurements. To facilitate greater application of the spectra, the library has also been convolved to selected spectrometer and imaging spectrometers sampling and

  12. Principal component analysis as a tool for library design: a case study investigating natural products, brand-name drugs, natural product-like libraries, and drug-like libraries.

    PubMed

    Wenderski, Todd A; Stratton, Christopher F; Bauer, Renato A; Kopp, Felix; Tan, Derek S

    2015-01-01

    Principal component analysis (PCA) is a useful tool in the design and planning of chemical libraries. PCA can be used to reveal differences in structural and physicochemical parameters between various classes of compounds by displaying them in a convenient graphical format. Herein, we demonstrate the use of PCA to gain insight into structural features that differentiate natural products, synthetic drugs, natural product-like libraries, and drug-like libraries, and show how the results can be used to guide library design.

  13. Art Libraries Section. Special Libraries Division. Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    Papers on art libraries and information services for the arts, which were presented at the 1983 International Federation of Library Associations (IFLA) conference, include: (1) "'I See All': Information Technology and the Universal Availability of Images" by Philip Pacey (United Kingdom); (2) "Online Databases in the Fine Arts"…

  14. Library Advocacy Now! Library Advocate's Handbook. [Videotape.

    ERIC Educational Resources Information Center

    American Library Association Video/Library Video Network, Towson, MD.

    Libraries are one of the world's greatest assets. Changes in the political, social, and economic climate in the U.S. mean that people cannot take public access to information for granted. Intense competition for public, private, and institutional dollars makes it more crucial than ever that policymakers understand that libraries--public, school,…

  15. Library Advocacy Now! Library Advocate's Handbook. [Videotape.

    ERIC Educational Resources Information Center

    American Library Association Video/Library Video Network, Towson, MD.

    Libraries are one of the world's greatest assets. Changes in the political, social, and economic climate in the U.S. mean that people cannot take public access to information for granted. Intense competition for public, private, and institutional dollars makes it more crucial than ever that policymakers understand that libraries--public, school,…

  16. Art Libraries Section. Special Libraries Division. Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    Papers on art libraries and information services for the arts, which were presented at the 1983 International Federation of Library Associations (IFLA) conference, include: (1) "'I See All': Information Technology and the Universal Availability of Images" by Philip Pacey (United Kingdom); (2) "Online Databases in the Fine Arts"…

  17. The Virtual Library: Computers in Libraries Canada.

    ERIC Educational Resources Information Center

    Saunders, Laverna

    1992-01-01

    Reports on a postconference workshop on virtual libraries that was presented at the third annual Computers in Libraries Canada Conference. Highlights include networks; technological change; administrative issues, including organizational structure, staff training, strategic planning, and financial resources; a case study of the University of…

  18. Administrative Libraries Section. Special Libraries Division. Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    Six papers on the theme, "Administrative Libraries in a Technological World: Past, Present, and Future--A General Stocktaking and a State of the Art Report" focus on West German telecommunications and information technology and the use of data processing and other technological aids in West German administrative libraries. These papers,…

  19. Combinatorial library-based design with Basis Products

    NASA Astrophysics Data System (ADS)

    Zhou, Joe Zhongxiang; Shi, Shenghua; Na, Jim; Peng, Zhengwei; Thacher, Tom

    2009-10-01

    Uncovering useful lead compounds from a vast virtual library of synthesizable compounds continues to be of tremendous interest to pharmaceutical researchers. Here we present the concept of Basis Products (BPs), a new and broadly applicable method for achieving efficient selections from a combinatorial library. By definition, Basis Products are a strategically selected subset of compounds from a potentially very large combinatorial library, and any compound in a combinatorial library can represented by its BPs. In this article we will show how to use BP docking scores to find the top compounds of a combinatorial library. Compared with the brute-force docking of an entire virtual library, docking with BPs are much more efficient because of the substantial size reduction, saving both time and resources. We will also demonstrate how BPs can be used for property-based combinatorial library designs. Furthermore, BPs can also be considered as fragments carrying chemistry knowledge, hence they can potentially be used in combination with any fragment-based design method. Therefore, BPs can be used to integrate combinatorial design with structure-based design and/or fragment-based design. Other potential applications of BPs include lead hopping and consensus core building, which we will describe briefly as well in this report.

  20. Community, Library, and Revolution

    ERIC Educational Resources Information Center

    Freiser, Leonard H.

    1970-01-01

    Discusses the need for greatly expanded community library services, for librarians to accept social responsibility for education and information, and for the library to become a program for getting information to where it is needed. (JS)

  1. Technology for Libraries.

    ERIC Educational Resources Information Center

    Phenix, Katharine; And Others

    1990-01-01

    Five articles discuss information technology in libraries: (1) "Software for Libraries" (Katharine Phenix); (2) "Online Update: European Online Services" (Martin Kesselman); (3) "Connect Time: Online Pricing Breakthroughs" (Barbara Quint); (4) "Microcomputing: Micro Biology Computer Viruses" (James LaRue);…

  2. Selecting Library Furniture & Equipment.

    ERIC Educational Resources Information Center

    Media & Methods, 1997

    1997-01-01

    Offers suggestions for selecting school library furniture and equipment. Describes various models of computer workstations; reading tables and chairs; and shelving. Sidebar lists names and addresses of library furniture manufactures and distributors. (AEF)

  3. Israeli Special Libraries

    ERIC Educational Resources Information Center

    Foster, Barbara

    1974-01-01

    Israel is sprinkled with a noteworthy representation of special libraries which run the gamut from modest kibbutz efforts to highly technical scientific and humanities libraries. A few examples are discussed here. (Author/CH)

  4. Small Libraries, Big Technology

    ERIC Educational Resources Information Center

    Roberts,Gary

    2005-01-01

    Small libraries don't have the resources to adopt every new technology. It is important that small libraries operate strategically, adopting only those technologies that are the most beneficial to their patrons.

  5. The Library Morphs

    ERIC Educational Resources Information Center

    Waters, John K.

    2008-01-01

    As campus renovation projects go, the Ohio State University's plan to turn its main library into "a library for the 21st century" is ambitious. The author describes the decade-long, $109 million transformation of the William Oxley Thompson Memorial Library. The overhaul calls for a complete replacement of all mechanical and electrical…

  6. Art for Libraries' Sake.

    ERIC Educational Resources Information Center

    Lugo, Mark-Elliot

    1999-01-01

    Illustrates the benefits of an aggressive library program of regularly scheduled and professionally curated art exhibitions and related events. Describes the Visual Arts Program at the Pacific Beach branch library (San Diego). A sidebar by Debra Wilcox Johnson discusses libraries' development of cultural programming for adults. (AEF)

  7. Marketing Academic Libraries

    ERIC Educational Resources Information Center

    Mallon, Melissa, Ed.

    2013-01-01

    Ask any academic librarian if marketing their library and its services is an important task, and the answer will most likely be a resounding "yes!" Particularly in economically troubled times, librarians are increasingly called upon to promote their services and defend their library's worth. Since few academic libraries have in-house marketing…

  8. Technology and Libraries.

    ERIC Educational Resources Information Center

    Cuadra, Carlos A.; And Others

    The application of technology to libraries, possible library systems of the future, and problems of effecting a transition between the present and the future are examined. The report identifies a series of recognized or assumed service and operations requirements, surveys major technologies applicable to libraries, and reviews current and planned…

  9. Libraries and the Environment.

    ERIC Educational Resources Information Center

    LaRue, James; And Others

    1991-01-01

    Three articles address issues that relate to libraries and the environment. Highlights include recycling projects; buying recycled paper products and other ecology-minded purchasing ideas; energy-efficient libraries; indoor pollution problems; a list of environmental information sources; designing library buildings; and activities that libraries…

  10. Library Community Services.

    ERIC Educational Resources Information Center

    Correy, Therese; And Others

    Services to the elderly, institutionalized, and physically and mentally exceptional, who are unable to use the public library in its traditional form, are described in this guide to programs at the Inglewood (California) Public Library. Topics include: (1) overall library goals and activities; (2) functional and organizational structure of…

  11. Special Libraries Division. Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    In "How Special Libraries Use Networks," a paper presented at the 1982 International Federation of Library Associations (IFLA) conference, David R. Bender (United States) advocates cooperation among academic, public, school, and special libraries in the areas of information management, staff services, and acquisition of technology. He…

  12. Library Journal Classics.

    ERIC Educational Resources Information Center

    Crunden, Frederick; And Others

    1993-01-01

    Includes four articles originally published in the 1890s. Highlights include a discussion of freedom of speech, political opinions, and the role of the public library in social reform; the establishment of a congressional or national library; censorship in libraries; and a criticism of a librarian by his assistant. (LRW)

  13. Library Journal Classics.

    ERIC Educational Resources Information Center

    Berninghausen, David; And Others

    1993-01-01

    Provides excerpts from David Berninghausens's "Social Responsibility vs. the Library Bill of Rights" and responses that appeared in "Library Journal" in 1972 and 1973 because of the continuing debate over the role of the American Library Association (ALA) Social Responsibilities Round Table and whether or not ALA should take…

  14. Worthington Libraries, OH

    ERIC Educational Resources Information Center

    Berry, John N., III

    2007-01-01

    Worthington, Ohio, has deep library roots. A library has been part of its history since the planning by settlers before the city's birth in 1803. Among the treasures brought by James Kilbourne and the Scioto Company from Connecticut to the new, planned community they built was a collection of books for their new subscription library. The books…

  15. Virtual Libraries: Service Realities.

    ERIC Educational Resources Information Center

    Novak, Jan

    2002-01-01

    Discussion of changes in society that have resulted from information and communication technologies focuses on changes in libraries and a new market for library services with new styles of clients. Highlights client service issues to be considered when transitioning to a virtual library situation. (Author/LRW)

  16. Spanish Museum Libraries Network.

    ERIC Educational Resources Information Center

    Lopez de Prado, Rosario

    This paper describes the creation of an automated network of museum libraries in Spain. The only way in which the specialized libraries in the world today can continue to be active and to offer valid information is to automate the service they offer, and create network libraries with cooperative plans. The network can be configured with different…

  17. School Libraries and Innovation

    ERIC Educational Resources Information Center

    McGrath, Kevin G.

    2015-01-01

    School library programs have measured success by improved test scores. But how do next-generation school libraries demonstrate success as they strive to be centers of innovation and creativity? These libraries offer solutions for school leaders who struggle to restructure existing systems built around traditional silos of learning (subjects and…

  18. The Library Morphs

    ERIC Educational Resources Information Center

    Waters, John K.

    2008-01-01

    As campus renovation projects go, the Ohio State University's plan to turn its main library into "a library for the 21st century" is ambitious. The author describes the decade-long, $109 million transformation of the William Oxley Thompson Memorial Library. The overhaul calls for a complete replacement of all mechanical and electrical…

  19. STRENGTHENING THE COLLEGE LIBRARY.

    ERIC Educational Resources Information Center

    JACOBS, KARL J.; TANIS, NORMAN E.

    A COMMITTEE AT HENRY FORD COMMUNITY COLLEGE WAS ESTABLISHED TO STUDY THE LIBRARY, FORMULATE AN EVALUATION, AND DEVELOP A SERIES OF RECOMMENDATIONS ISSUING OUT OF AND BASED ON THE STUDY. THE COMMITTEE USED THE JUNIOR COLLEGE LIBRARY STANDARDS AS THE INSTRUMENT FOR JUDGING THE LIBRARY PROGRAM. FROM EACH OF THE EIGHT SECTIONS OF THE STANDARDS, THEY…

  20. LIBRARY SYSTEMS ANALYSIS.

    ERIC Educational Resources Information Center

    HIEBER, CAROLINE E.; TAYLOR, ROBERT S.

    STEPS THAT THE LIBRARY CAN TAKE IN PREPARING FOR A CHANGE TO AN AUTOMATED SYSTEM WERE INVESTIGATED. THE METHOD DESCRIBED WAS BASED ON AN ANALYSIS OF CLERICAL AND OFFICE WORK CALLED INTEGRATED PROCEDURES OF CONTROL (IPC). THE APPLICATION OF LIBRARY SYSTEMS ANALYSIS (LISA) TO THE LEHIGH UNIVERSITY LIBRARY IS DESCRIBED. THIS PROCESS INVOLVED (1)…

  1. Revolution in the Library.

    ERIC Educational Resources Information Center

    Himmelfarb, Gertrude

    1999-01-01

    There is an electronic revolution in the library which may prove to be a revolution in the humanities and in the nature of learning and education. The humanities are an essentially human enterprise of which the record reposes in books in libraries. The central role of libraries in preserving these ideas must survive the electronic revolution.…

  2. California Library Laws, 2009

    ERIC Educational Resources Information Center

    Smith, Paul G., Ed.

    2009-01-01

    California Library Laws 2009 is a selective guide to state laws and related materials that most directly affect the everyday operations of public libraries and organizations that work with public libraries. It is intended as a convenient reference, not as a replacement for the annotated codes or for legal advice. The guide is organized as follows.…

  3. California Library Laws, 2008

    ERIC Educational Resources Information Center

    Smith, Paul G., Ed.

    2008-01-01

    "California Library Laws 2008" is a selective guide to state laws and related materials that most directly affect the everyday operations of public libraries and organizations that work with public libraries. It is intended as a convenient reference, not as a replacement for the annotated codes or for legal advice. The guide is organized…

  4. Digital Libraries: An Overview.

    ERIC Educational Resources Information Center

    Schwartz, Candy

    2000-01-01

    Provides an overview of the basic components of a digital library. Highlights include library collections; metadata; services, including information seeking and retrieval, reference query fulfillment, and user training; user interaction with digital libraries, including searching, browsing, and navigation; economic support; maintenance;…

  5. Merchandising Your Library.

    ERIC Educational Resources Information Center

    Sivulich, Kenneth G.

    1989-01-01

    Discusses library circulation figures as a reflection of the success of library services and describes merchandising techniques that have produced a 137 percent circulation increase at Queens Borough Public Library over the past seven years. Merchandising techniques such as minibranches, displays, signage, dumps, and modified shelving are…

  6. Workbook in Library Skills.

    ERIC Educational Resources Information Center

    Wright, Nancy Kirkpatrick

    This workbook, designed for a library skills course, provides 23 lessons to acquaint Yavapai College (YC) students with basic library reference skills. Each lesson begins with explanatory text, followed by reinforcement exercises. After providing course information, the workbook offers information on using the library (Lesson 1), finding books in…

  7. Place as Library?

    ERIC Educational Resources Information Center

    Davenport, Nancy

    2006-01-01

    Digital technology is redrawing the library's blueprint. Planners are thinking in new ways about how to design libraries as places for learning rather than primarily as storehouses of information. This thinking has given rise to much discussion--and to many publications--about the "library as place." In this article, the author asks why not also…

  8. Worthington Libraries, OH

    ERIC Educational Resources Information Center

    Berry, John N., III

    2007-01-01

    Worthington, Ohio, has deep library roots. A library has been part of its history since the planning by settlers before the city's birth in 1803. Among the treasures brought by James Kilbourne and the Scioto Company from Connecticut to the new, planned community they built was a collection of books for their new subscription library. The books…

  9. The Michigan Electronic Library.

    ERIC Educational Resources Information Center

    Davidsen, Susanna L.

    1997-01-01

    Describes the Michigan Electronic Library (MEL), the largest evaluated and organized Web-based library of Internet resources, that was designed to provide a library of electronic information resources selected by librarians. MEL's partnership is explained, the collection is described, and future developments are considered. (LRW)

  10. Library Community Services.

    ERIC Educational Resources Information Center

    Correy, Therese; And Others

    Services to the elderly, institutionalized, and physically and mentally exceptional, who are unable to use the public library in its traditional form, are described in this guide to programs at the Inglewood (California) Public Library. Topics include: (1) overall library goals and activities; (2) functional and organizational structure of…

  11. School Library Policy Statement.

    ERIC Educational Resources Information Center

    Manitoba Dept. of Education, Winnipeg. Instructional Resources Branch.

    The School Library Policy Statement for Manitoba schools begins with the mission statement of Manitoba Education and Training and the Goals of Learning for Manitoba. Statements of Manitoba's School Library Policy and the Philosophy of the School Library Program are also provided, together with an outline of the responsibilities of both Manitoba's…

  12. Public Libraries Going Green

    ERIC Educational Resources Information Center

    Miller, Kathryn

    2010-01-01

    Going green is now a national issue, and patrons expect their library to respond in the same way many corporations have. Libraries are going green with logos on their Web sites, programs for the public, and a host of other initiatives. This is the first book to focus strictly on the library's role in going green, helping you with: (1) Collection…

  13. Supervision in Libraries.

    ERIC Educational Resources Information Center

    Bailey, Martha J.

    Although the literature of library administration draws extensively on that of business management, it is difficult to compare library supervision to business or industrial supervision. Library supervisors often do not have managerial training and may consider their management role as secondary. The educational level of the staff they supervise…

  14. The Occasional Library Newsletter

    ERIC Educational Resources Information Center

    Gustafson, Chris

    2004-01-01

    An important tool for communication and collaboration is the library newsletter, which the library media specialist writes to the staff, teachers and library media specialist from other schools. The newsletter includes upcoming events teachers can sign up for, information on web sites to be used for projects, curriculum ideas, introduction of a…

  15. Technostress and Library Values.

    ERIC Educational Resources Information Center

    Gorman, Michael

    2001-01-01

    Discusses information overload and society's and libraries' responses to technology. Considers eight values that libraries should focus on and how they relate to technology in libraries: democracy, stewardship, service, intellectual freedom, privacy, rationalism, equity of access, and building harmony and balance. (LRW)

  16. Virtual Libraries: Service Realities.

    ERIC Educational Resources Information Center

    Novak, Jan

    2002-01-01

    Discussion of changes in society that have resulted from information and communication technologies focuses on changes in libraries and a new market for library services with new styles of clients. Highlights client service issues to be considered when transitioning to a virtual library situation. (Author/LRW)

  17. Using the Presidential Libraries.

    ERIC Educational Resources Information Center

    Dollase, Richard H.

    1984-01-01

    Research and learning opportunities for elementary and secondary students at the seven presidential libraries located around the country are discussed. A questionnaire was sent to each institution, and several of the libraries were visited. Also presented is an overview of the presidential library system. (RM)

  18. Roster of Federal Libraries.

    ERIC Educational Resources Information Center

    Benton, Mildred, Comp.; Ottersen, Signe, Comp.

    This Roster of Federal Libraries represents an attempt by the Federal Library Committee to identify each of the more than 1,900 individual libraries serving the many departments, committees, agencies, courts, and other formal organizational entities in the Federal Government. They include six types: Presidential, national, general, academic,…

  19. Library Studies I Workbook.

    ERIC Educational Resources Information Center

    Frost, William J.

    Developed for use in the Library Studies I component of the Library Studies Program at Bloomsburg University (Pennsylvania), this self-paced workbook is intended to acquaint students with the Harvey A. Andruss Library and help them develop information-seeking skills. The workbook is designed to be used in conjunction with an exercise book, and…

  20. The Occasional Library Newsletter

    ERIC Educational Resources Information Center

    Gustafson, Chris

    2004-01-01

    An important tool for communication and collaboration is the library newsletter, which the library media specialist writes to the staff, teachers and library media specialist from other schools. The newsletter includes upcoming events teachers can sign up for, information on web sites to be used for projects, curriculum ideas, introduction of a…

  1. Marketing Academic Libraries

    ERIC Educational Resources Information Center

    Mallon, Melissa, Ed.

    2013-01-01

    Ask any academic librarian if marketing their library and its services is an important task, and the answer will most likely be a resounding "yes!" Particularly in economically troubled times, librarians are increasingly called upon to promote their services and defend their library's worth. Since few academic libraries have in-house marketing…

  2. Technostress and Library Values.

    ERIC Educational Resources Information Center

    Gorman, Michael

    2001-01-01

    Discusses information overload and society's and libraries' responses to technology. Considers eight values that libraries should focus on and how they relate to technology in libraries: democracy, stewardship, service, intellectual freedom, privacy, rationalism, equity of access, and building harmony and balance. (LRW)

  3. Tomorrow's Library Today.

    ERIC Educational Resources Information Center

    Penniman, W. David

    1987-01-01

    Presents a model for predicting and shaping the impact of information technologies on libraries and the library role which is based on the effects of computerization in various business applications. The library network at AT&T Bell Laboratories is described as an example of a successful implementation of the model. (CLB)

  4. PAL: Positional Astronomy Library

    NASA Astrophysics Data System (ADS)

    Jenness, T.; Berry, D. S.

    2016-06-01

    The PAL library is a partial re-implementation of Pat Wallace's popular SLALIB library written in C using a Gnu GPL license and layered on top of the IAU's SOFA library (or the BSD-licensed ERFA) where appropriate. PAL attempts to stick to the SLA C API where possible.

  5. Managing Public Library Investments.

    ERIC Educational Resources Information Center

    Sager, Don

    1985-01-01

    Reports results of public library survey conducted by a Public Library Association committee that was established to study library investment practices and assess the need for establishing an investment management service. Revenue sources, investment patterns, benefits of pooling, and a proposed management service are highlighted. Six sources are…

  6. A Truly Bookless Library

    ERIC Educational Resources Information Center

    Kolowich, Steve

    2011-01-01

    The difference between the University of Texas at San Antonio's Applied Engineering and Technology Library and other science-focused libraries is not that its on-site collection is also available electronically. It is that its on-site collection is only available electronically. The idea of libraries with no bound books has been a recurring theme…

  7. Summer Library Reading Programs

    ERIC Educational Resources Information Center

    Fiore, Carole D.

    2007-01-01

    Virtually all public libraries in the United States provide some type of summer library reading program during the traditional summer vacation period. Summer library reading programs provide opportunities for students of many ages and abilities to practice their reading skills and maintain skills that are developed during the school year. Fiore…

  8. Characteristics of Corporate Libraries.

    ERIC Educational Resources Information Center

    Charny, Wendy

    This paper reports on a study conducted to collect the data pertaining to corporate libraries in the United States in order to provide a statistical profile of these special libraries. A review of the literature was performed. The researcher used the online "1996 Directory of Special Libraries and Information Centers," which lists 21,380…

  9. Changing State Digital Libraries

    ERIC Educational Resources Information Center

    Pappas, Marjorie L.

    2006-01-01

    Research has shown that state virtual or digital libraries are evolving into websites that are loaded with free resources, subscription databases, and instructional tools. In this article, the author explores these evolving libraries based on the following questions: (1) How user-friendly are the state digital libraries?; (2) How do state digital…

  10. Concepts of Library Goodness.

    ERIC Educational Resources Information Center

    Buckland, Michael K.

    1982-01-01

    Orr's schema for measuring the quality and value of libraries is described and discussed with respect to three paradoxes--the evaluation of catalogs, optimal library size, and Lenin's view of public libraries in the U.S. Seven references are cited. (CHC)

  11. School Libraries and Innovation

    ERIC Educational Resources Information Center

    McGrath, Kevin G.

    2015-01-01

    School library programs have measured success by improved test scores. But how do next-generation school libraries demonstrate success as they strive to be centers of innovation and creativity? These libraries offer solutions for school leaders who struggle to restructure existing systems built around traditional silos of learning (subjects and…

  12. Public Libraries Going Green

    ERIC Educational Resources Information Center

    Miller, Kathryn

    2010-01-01

    Going green is now a national issue, and patrons expect their library to respond in the same way many corporations have. Libraries are going green with logos on their Web sites, programs for the public, and a host of other initiatives. This is the first book to focus strictly on the library's role in going green, helping you with: (1) Collection…

  13. Educating the Library User.

    ERIC Educational Resources Information Center

    Lubans, John, Jr.

    A collection of original essays, case studies, and research reports is presented on the problems, hopes, and techniques of instructing library users and nonusers, from the kindergartener to the postschool adult, in the effective use of libraries and their resources. First there is a comprehensive overview of the research to date on library user…

  14. Library Building and Design.

    ERIC Educational Resources Information Center

    Jones, David J.; Gordon, Heather; Caddy, Julie; Kahlert, Maureen; Johnson, Carolyn; Holdstock, Fiona

    1997-01-01

    More frequently, community connections are being expressed in library design briefs and reflected in the completed buildings. This collection of brief articles discusses community involvement in library design and services and describes library construction projects in Australia and Malaysia. Also, discusses community art programs, integrating…

  15. New York Zoological Society Library.

    ERIC Educational Resources Information Center

    Johnson, Steven P.

    1988-01-01

    Describes the institutional setting, history, and services of the New York Zoological Society Library. Topics covered include clientele; library collections and special collections; library staffing and organizational structure; computer applications; and relationships with other libraries. (11 references) (CLB)

  16. Small-Molecule Library Subset Screening as an Aid for Accelerating Lead Identification.

    PubMed

    Beresini, Maureen H; Liu, Yichin; Dawes, Timothy D; Clark, Kevin R; Orren, Linda; Schmidt, Stephen; Turincio, Rebecca; Jones, Steven W; Rodriguez, Richard A; Thana, Peter; Hascall, Daniel; Gross, Daniel P; Skelton, Nicholas J

    2014-06-01

    Several small-compound library subsets (14,000 to 56,000) have been established to complement screening of a larger Genentech corporate library (~1,300,000). Two validation sets (~1% of the total library) containing compounds representative of the main library were chosen by selection of plates or individual compounds. Use of these subsets guided selection of assay configuration, validated assay reproducibility, and provided estimates of hit rates expected from our full library. A larger diversity subset representing the scaffold diversity of the full library (3.4% of the total) was designed for screening more challenging targets with limited reagent availability or low-throughput assays. Retrospective analysis of this subset showed hit rates similar to those of the main library while recovering a higher proportion of hit scaffolds. Finally, a property-restricted diversity set called the "in-between library" was established to identify ligand-efficient compounds of molecular size between those typically found in fragment and high-throughput screening libraries. It was screened at fivefold higher concentrations than the main library to facilitate identification of less potent yet ligand-efficient compounds. Taken together, this work underscores the value of generating multiple purpose-focused, diversity-based library subsets that are designed using computational approaches coupled with internal screening data analyses to accelerate the lead discovery process. © 2014 Society for Laboratory Automation and Screening.

  17. Cost Differentials between E-Books and Print in Academic Libraries

    ERIC Educational Resources Information Center

    Bailey, Timothy P.; Scott, Amanda L.; Best, Rickey D.

    2015-01-01

    Academic libraries continue to face funding pressures compounded by the need to provide students with access to electronic resources, both in journal and book formats. With space constraints and the need to repurpose library space to other uses, libraries must carefully examine the move to e-only formats for books to determine if the format makes…

  18. Cost Differentials between E-Books and Print in Academic Libraries

    ERIC Educational Resources Information Center

    Bailey, Timothy P.; Scott, Amanda L.; Best, Rickey D.

    2015-01-01

    Academic libraries continue to face funding pressures compounded by the need to provide students with access to electronic resources, both in journal and book formats. With space constraints and the need to repurpose library space to other uses, libraries must carefully examine the move to e-only formats for books to determine if the format makes…

  19. [Status of libraries and databases for natural products at abroad].

    PubMed

    Zhao, Li-Mei; Tan, Ning-Hua

    2015-01-01

    For natural products are one of the important sources for drug discovery, libraries and databases of natural products are significant for the development and research of natural products. At present, most of compound libraries at abroad are synthetic or combinatorial synthetic molecules, resulting to access natural products difficult; for information of natural products are scattered with different standards, it is difficult to construct convenient, comprehensive and large-scale databases for natural products. This paper reviewed the status of current accessing libraries and databases for natural products at abroad and provided some important information for the development of libraries and database for natural products.

  20. Discovery libraries targeting the major enzyme classes: the serine hydrolases.

    PubMed

    Otrubova, Katerina; Srinivasan, Venkat; Boger, Dale L

    2014-08-15

    Two libraries of modestly reactive ureas containing either electron-deficient acyl anilines or acyl pyrazoles were prepared and are reported as screening libraries for candidate serine hydrolase inhibitors. Within each library is a small but powerful subset of compounds that serve as a chemotype fragment screening library capable of subsequent structural diversification. Elaboration of the pyrazole-based ureas provided remarkably potent irreversible inhibitors of fatty acid amide hydrolase (FAAH, apparent Ki=100-200 pM) complementary to those previously disclosed enlisting electron-deficient aniline-based ureas.

  1. Discovery libraries targeting the major enzyme classes: the serine hydrolases

    PubMed Central

    Otrubova, Katerina; Srinivasan, Venkat; Boger, Dale L.

    2014-01-01

    Two libraries of modestly reactive ureas containing either electron-deficient acyl anilines or acyl pyrazoles were prepared and are reported as screening libraries for candidate serine hydrolase inhibitors. Within each library is a small but powerful subset of compounds that serve as a chemotype fragment screening library capable of subsequent diversification. Elaboration of the pyrazole-based ureas provided remarkably potent irreversible structural inhibitors of fatty acid amide hydrolase (FAAH, apparent Ki = 100-200 pM) complementary to those previously disclosed enlisting electron-deficient aniline-based ureas. PMID:25037918

  2. Multipin technology in the preparation and screening of peptide libraries.

    PubMed

    Rodda, S J; Mason, T J; Maeji, N J

    1993-01-01

    Peptide libraries are relatively new sources of enormous numbers of unique compounds, fodder for the mill of drug discovery programs. Their enormous diversity derives from vast numbers of combinations of a small number of monomers (Geysen et al., 1986). For example, a complete hexapeptide library synthesized from just 10 monomers (amino acids) has one million unique compounds in it. In principle, other types of combinatorial libraries can have equally vast numbers of members; for example, the monomers can be N-acyl glycines, giving rise to the so-called "peptoids" (Simon et al., 1992); or the monomers could be monosaccharides or nucleotides.

  3. DNA-encoded chemical libraries: advancing beyond conventional small-molecule libraries.

    PubMed

    Franzini, Raphael M; Neri, Dario; Scheuermann, Jörg

    2014-04-15

    DNA-encoded chemical libraries (DECLs) represent a promising tool in drug discovery. DECL technology allows the synthesis and screening of chemical libraries of unprecedented size at moderate costs. In analogy to phage-display technology, where large antibody libraries are displayed on the surface of filamentous phage and are genetically encoded in the phage genome, DECLs feature the display of individual small organic chemical moieties on DNA fragments serving as amplifiable identification barcodes. The DNA-tag facilitates the synthesis and allows the simultaneous screening of very large sets of compounds (up to billions of molecules), because the hit compounds can easily be identified and quantified by PCR-amplification of the DNA-barcode followed by high-throughput DNA sequencing. Several approaches have been used to generate DECLs, differing both in the methods used for library encoding and for the combinatorial assembly of chemical moieties. For example, DECLs can be used for fragment-based drug discovery, displaying a single molecule on DNA or two chemical moieties at the extremities of complementary DNA strands. DECLs can vary substantially in the chemical structures and the library size. While ultralarge libraries containing billions of compounds have been reported containing four or more sets of building blocks, also smaller libraries have been shown to be efficient for ligand discovery. In general, it has been found that the overall library size is a poor predictor for library performance and that the number and diversity of the building blocks are rather important indicators. Smaller libraries consisting of two to three sets of building blocks better fulfill the criteria of drug-likeness and often have higher quality. In this Account, we present advances in the DECL field from proof-of-principle studies to practical applications for drug discovery, both in industry and in academia. DECL technology can yield specific binders to a variety of target

  4. Flight Software Math Library

    NASA Technical Reports Server (NTRS)

    McComas, David

    2013-01-01

    The flight software (FSW) math library is a collection of reusable math components that provides typical math utilities required by spacecraft flight software. These utilities are intended to increase flight software quality reusability and maintainability by providing a set of consistent, well-documented, and tested math utilities. This library only has dependencies on ANSI C, so it is easily ported. Prior to this library, each mission typically created its own math utilities using ideas/code from previous missions. Part of the reason for this is that math libraries can be written with different strategies in areas like error handling, parameters orders, naming conventions, etc. Changing the utilities for each mission introduces risks and costs. The obvious risks and costs are that the utilities must be coded and revalidated. The hidden risks and costs arise in miscommunication between engineers. These utilities must be understood by both the flight software engineers and other subsystem engineers (primarily guidance navigation and control). The FSW math library is part of a larger goal to produce a library of reusable Guidance Navigation and Control (GN&C) FSW components. A GN&C FSW library cannot be created unless a standardized math basis is created. This library solves the standardization problem by defining a common feature set and establishing policies for the library s design. This allows the libraries to be maintained with the same strategy used in its initial development, which supports a library of reusable GN&C FSW components. The FSW math library is written for an embedded software environment in C. This places restrictions on the language features that can be used by the library. Another advantage of the FSW math library is that it can be used in the FSW as well as other environments like the GN&C analyst s simulators. This helps communication between the teams because they can use the same utilities with the same feature set and syntax.

  5. Rapid Discovery of Functional Small Molecule Ligands against Proteomic Targets through Library-Against-Library Screening

    PubMed Central

    2016-01-01

    Identifying “druggable” targets and their corresponding therapeutic agents are two fundamental challenges in drug discovery research. The one-bead-one-compound (OBOC) combinatorial library method has been developed to discover peptides or small molecules that bind to a specific target protein or elicit a specific cellular response. The phage display cDNA expression proteome library method has been employed to identify target proteins that interact with specific compounds. Here, we combined these two high-throughput approaches, efficiently interrogated approximately 1013 possible molecular interactions, and identified 91 small molecule compound beads that interacted strongly with the phage library. Of 19 compounds resynthesized, 4 were cytotoxic against cancer cells; one of these compounds was found to interact with EIF5B and inhibit protein translation. As more binding pairs are confirmed and evaluated, the “library-against-library” screening approach and the resulting small molecule–protein domain interaction database may serve as a valuable tool for basic research and drug development. PMID:27053324

  6. Mining the ChEMBL database: an efficient chemoinformatics workflow for assembling an ion channel-focused screening library.

    PubMed

    Mok, N Yi; Brenk, Ruth

    2011-10-24

    The ChEMBL database was mined to efficiently assemble an ion channel-focused screening library. The compiled library consists of 3241 compounds representing 123 templates across nine ion channel categories. Compounds in the screening library are annotated with their respective ion channel category to facilitate back-tracing of prospective molecular targets from phenotypic screening results. The established workflow is adaptable to the construction of focused screening libraries for other therapeutic target classes with diverse recognition motifs.

  7. Assessing Library Automation and Virtual Library Development in Four Academic Libraries in Oyo, Oyo State, Nigeria

    ERIC Educational Resources Information Center

    Gbadamosi, Belau Olatunde

    2011-01-01

    The paper examines the level of library automation and virtual library development in four academic libraries. A validated questionnaire was used to capture the responses from academic librarians of the libraries under study. The paper discovers that none of the four academic libraries is fully automated. The libraries make use of librarians with…

  8. Enriching screening libraries with bioactive fragment space.

    PubMed

    Zhang, Na; Zhao, Hongtao

    2016-08-01

    By deconvoluting 238,073 bioactive molecules in the ChEMBL library into extended Murcko ring systems, we identified a set of 2245 ring systems present in at least 10 molecules. These ring systems belong to 2221 clusters by ECFP4 fingerprints with a minimum intracluster similarity of 0.8. Their overlap with ring systems in commercial libraries was further quantified. Our findings suggest that success of a small fragment library is driven by the convergence of effective coverage of bioactive ring systems (e.g., 10% coverage by 1000 fragments vs. 40% by 2million HTS compounds), high enrichment of bioactive ring systems, and low molecular complexity enhancing the probability of a match with the protein targets. Reconciling with the previous studies, bioactive ring systems are underrepresented in screening libraries. As such, we propose a library of virtual fragments with key functionalities via fragmentation of bioactive molecules. Its utility is exemplified by a prospective application on protein kinase CK2, resulting in the discovery of a series of novel inhibitors with the most potent compound having an IC50 of 0.5μM and a ligand efficiency of 0.41kcal/mol per heavy atom. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Integration of Library Services in the System of Digital Libraries

    NASA Astrophysics Data System (ADS)

    Bezdushnyj, A. N.; Kalenov, N. E.; Kouriv, P. M.; Serebryakov, V. A.

    The article is devoted to the functional extension of the Integrated System of Information Resources of RAS (ISIR RAS - RFBR 99-07-90139 project). This extension (Library Subsystem) provides integration of library services in ISIR RAS electronic libraries system. Library Subsystem implements standard library services such as information about free and ordered copies of editions, creation of the library orders for edition etc. The Library Subsystem is an integrated solution; it's based on ISIR data model and technologies.

  10. IAC Library: Some Challenges

    NASA Astrophysics Data System (ADS)

    Gomez, M.

    2010-10-01

    Since its beginnings in 1985, the IAC Library has evolved from a traditional library where the physical place and collections were essential, to a hybrid library where users can often get what they need without going to the library. In this paper, we present how the various changes due to information technology advances that occurred in the 1990s, followed by a series of works carried out from 2004 to 2008 at IAC, as well as several internal and external events or decisions, have led the IAC Library to face three new challenges. First, as the library building has been enlarged and new spaces are now available for users and for shelving, we have to decide what we should we do with the new spaces. How we can make them attractive for users at a time when users often don't need to visit the library to access the information they need? Second, as IAC will implement a new integrated information system, we have an opportunity to define how the library system will participate within the IAC global information system, bringing to this great project our knowledge of information management, essential to improve the actual processes. Third, as the Ministry has created a working group on access to electronic resources, with participation by seven affiliated research institutions, we have, as a member of this group, to define how to deal with the Ministry and the other centres to set a library policy that will benefit the IAC Library.

  11. libdrdc: software standards library

    NASA Astrophysics Data System (ADS)

    Erickson, David; Peng, Tie

    2008-04-01

    This paper presents the libdrdc software standards library including internal nomenclature, definitions, units of measure, coordinate reference frames, and representations for use in autonomous systems research. This library is a configurable, portable C-function wrapped C++ / Object Oriented C library developed to be independent of software middleware, system architecture, processor, or operating system. It is designed to use the automatically-tuned linear algebra suite (ATLAS) and Basic Linear Algebra Suite (BLAS) and port to firmware and software. The library goal is to unify data collection and representation for various microcontrollers and Central Processing Unit (CPU) cores and to provide a common Application Binary Interface (ABI) for research projects at all scales. The library supports multi-platform development and currently works on Windows, Unix, GNU/Linux, and Real-Time Executive for Multiprocessor Systems (RTEMS). This library is made available under LGPL version 2.1 license.

  12. Academic Libraries, 2000. E.D. Tabs.

    ERIC Educational Resources Information Center

    Carey, Nancy; Justh, Natalie M.; Williams, Jeffrey W.

    This report discusses the state of academic libraries in 2000. It defines "academic library" as well as discusses library services, library collections, library staff, library expenditures, and electronic services. (Author/AMT)

  13. I.D. Weeks Library: Guide to Library Resources.

    ERIC Educational Resources Information Center

    South Dakota Univ., Vermillion. I.D. Weeks Library.

    This document is a guide to library resources in the I. D. Weeks Library at the University of South Dakota, Vermillion. The guide was designed to accompany an academic library instruction course, "Use of Library Resources, A & S 111." The purpose of the course is to familiarize students with the facilities of the I. D. Weeks Library;…

  14. A Directory of Library Instruction Programs in Indiana Academic Libraries.

    ERIC Educational Resources Information Center

    Skinner, Jane, Comp.; Violette, Judith, Comp.

    A survey of 40 reporting academic libraries in Indiana developed this directory of library user instruction programs which provides an index profile of library resources and types of programs within the state. Entries are alphabetical in outline form and provide a library contact person, capsule information about the library instruction program,…

  15. Standards for Medical Library Technicians, Medical Library Association.

    ERIC Educational Resources Information Center

    Medical Library Association, Chicago, IL.

    A medical library technician is a semiprofessional library employee whose duties require knowledge and skill based on a minimum of two years' general college education that includes library instruction beyond the clerical level. The medical library technician must have a practical knowledge of library functions and services, an understanding of…

  16. TRIFLUOROMETHYL COMPOUNDS OF GERMANIUM

    DTIC Science & Technology

    FLUORIDES, *GERMANIUM COMPOUNDS, *HALIDES, *ORGANOMETALLIC COMPOUNDS, ALKYL RADICALS, ARSENIC COMPOUNDS, CHEMICAL BONDS, CHEMICAL REACTIONS ...CHLORIDES, CHLORINE COMPOUNDS, HYDROLYSIS, IODIDES, METHYL RADICALS, POTASSIUM COMPOUNDS, PYROLYSIS, STABILITY, SYNTHESIS, TIN COMPOUNDS.

  17. Integrated circuit cell library

    NASA Technical Reports Server (NTRS)

    Whitaker, Sterling R. (Inventor); Miles, Lowell H. (Inventor)

    2005-01-01

    According to the invention, an ASIC cell library for use in creation of custom integrated circuits is disclosed. The ASIC cell library includes some first cells and some second cells. Each of the second cells includes two or more kernel cells. The ASIC cell library is at least 5% comprised of second cells. In various embodiments, the ASIC cell library could be 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more comprised of second cells.

  18. NEIC Library Services

    EPA Pesticide Factsheets

    The National Enforcement Investigation Center (NEIC) Environmental Forensic Library partners with NEIC's forensic scientists to retrieve, validate and deliver information to develop methods, defensible regulations, and environmental measurements.

  19. Automated Library System Specifications.

    DTIC Science & Technology

    1986-06-01

    AD-A78 95 AUTOMATED LIBRARY SYSTEM SPECIFICATIONS(U) ARMY LIBRARY /i MANAGEMENT OFFICE ALEXANDRIA VA ASSISTANT CHIEF OF STAFF FOR INFORMATION... MANAGEMENT M B BONNETT JUN 86 UNCLASSIFIED F/G 9/2 NLEElIIhllEEEEE IllEEEEEllllEI .1lm lliml * ~I fI.L25 MI, [OCM RL,;OCLUTO fl. ’N k~ AUTOMATED LIBRARY...SYSTEM SPECIFICATIONS .,I Prepared by Mary B. Bonnett ARMY LIBRARY MANAGEMENT OFFICE OFFICE OF THE ASSISTANT CHIEF OF STAFF FOR INFORMATION MANAGEMENT Lij

  20. A Distinct Subfraction of Aβ is Responsible for the High-Affinity Pittsburgh Compound B (PIB) Binding Site in Alzheimer’s Disease Brain

    PubMed Central

    Matveev, Sergey V.; Spielmann, H. Peter; Metts, Brittney M.; Chen, Jing; Onono, Fredrick; Zhu, Haining; Scheff, Stephen W.; Walker, Lary C.; LeVine, Harry

    2014-01-01

    The positron emitting (PET) 11C-labeled Pittsburgh Compound B (PIB) ligand is used to image β-amyloid (Aβ) deposits in the brains of living subjects with the intent of detecting early stages of Alzheimer’s disease (AD). However, deposits of human-sequence Aβ in APP transgenic mice and nonhuman primates bind very little PIB. The high stoichiometry of PIB:Aβ binding in human AD suggests that the PIB binding site may represent a particularly pathogenic entity and/or report local pathologic conditions. In this study, 3H-PIB was employed to track purification of the PIB binding site in > 90% yield from frontal cortical tissue of autopsy-diagnosed AD subjects. The purified PIB binding site comprises a distinct, highly insoluble subfraction of the Aβ in AD brain with low buoyant density due to an SDS-resistant association with a limited subset of brain proteins and lipids with physical properties similar to lipid rafts and to a ganglioside:Aβ complex in AD and Down Syndrome brain. Both the protein and lipid components are required for PIB binding. Elucidation of human-specific biological components and pathways will be important in guiding improvement of the animal models for AD and in identifying new potential therapeutic avenues. PMID:24995708

  1. Library Latchkey Children. ERIC Digest.

    ERIC Educational Resources Information Center

    Dowd, Frances Smardo

    This digest discusses ways in which public libraries deal with latchkey children who spend their after-school hours at public libraries while their parents are at work. Research conducted in 1990 of 110 public libraries revealed that almost all libraries encountered unattended children after school hours, and that most libraries surveyed were not…

  2. Public Relations in Special Libraries.

    ERIC Educational Resources Information Center

    Rutkowski, Hollace Ann; And Others

    1991-01-01

    This theme issue includes 11 articles on public relations (PR) in special libraries. Highlights include PR at the Special Libraries Association (SLA); sources for marketing research for libraries; developing a library image; sample PR releases; brand strategies for libraries; case studies; publicizing a consortium; and a bibliography of pertinent…

  3. A Tale of Two Libraries.

    ERIC Educational Resources Information Center

    Martinez, Ed

    1999-01-01

    Reviews the profiles of a typical public library, the Redondo Beach Public Library (California), and its nearby community college library, the Schauerman Library at El Camino College in Torrance, California. Discusses similarities between staff in public and academic libraries; differences between the two environments; and like missions of both…

  4. Central Statistical Libraries in Europe.

    ERIC Educational Resources Information Center

    Kaiser, Lisa

    The paper tries to clarify the position special governmental libraries hold in the system of libraries of today by investigating only one specific type of library mainly from a formal and historical point of view. Central statistical libraries in Europe were first regarded as administrative and archival libraries. Their early holdings of foreign…

  5. Handbook for Library Volunteers. Rev.

    ERIC Educational Resources Information Center

    San Bruno Park School District, San Bruno, CA.

    The functions and responsibilities of a school library and of the library personnel are presented in this handbook for parent library volunteers. Topics covered are: (1) the role of the library media center; (2) an outline of a volunteer's duties and daily routines; (3) the responsibilities of the district library specialist, the teacher, and the…

  6. Optical Disc Applications in Libraries.

    ERIC Educational Resources Information Center

    Andre, Pamela Q. J.

    1989-01-01

    Discusses a variety of library applications of optical disc storage technology, including CD-ROM, digital videodisc, and WORM. Research and development projects at the Library of Congress, National Library of Medicine, and National Agricultural Library are described, products offered by library networks are reviewed, and activities in academic and…

  7. Suggestions for Library Network Design.

    ERIC Educational Resources Information Center

    Salton, Gerald

    1979-01-01

    Various approaches to the design of automatic library systems are described, suggestions for the design of rational and effective automated library processes are posed, and an attempt is made to assess the importance and effect of library network systems on library operations and library effectiveness. (Author/CWM)

  8. Houston Cole Library Policy Manual.

    ERIC Educational Resources Information Center

    Henderson, William Abbot, Ed.

    This policy manual of Jacksonville State University's Houston Cole Library serves as a statement of the library's mission, goals, and objectives; an interpretive guide for library faculty, staff, and students; and informational document for library patrons concerning the library's programs and policies. The contents include the following:…

  9. Music Libraries: Centralization versus Decentralization.

    ERIC Educational Resources Information Center

    Kuyper-Rushing, Lois

    2002-01-01

    Considers the decision that branch libraries, music libraries in particular, have struggled with concerning a centralized location in the main library versus a decentralized collection. Reports on a study of the Association of Research Libraries that investigated the location of music libraries, motivation for the location, degrees offered,…

  10. Wisconsin Library Service Record, 1978.

    ERIC Educational Resources Information Center

    Wisconsin State Dept. of Public Instruction, Madison. Div. of Library Services.

    Narrative description and updated statistical tables cover all types of libraries and library related activities in the state. Major areas reported on are the Wisconsin library network, including planning, media services, and special services for children, the institutionalized, and handicapped; library and media organizations; library education,…

  11. Wisconsin Library Service Record, 1974.

    ERIC Educational Resources Information Center

    Wisconsin State Dept. of Public Instruction, Madison. Div. of Library Services.

    In a record of library activities in Wisconsin in 1974, the activities of the Division for Library Services are described along with the Wisconsin Library Network and the state and regional library networks, services, and resources. Lists of library and media organizations and education programs are followed by a directory of academic, public,…

  12. A Tale of Two Libraries.

    ERIC Educational Resources Information Center

    Martinez, Ed

    1999-01-01

    Reviews the profiles of a typical public library, the Redondo Beach Public Library (California), and its nearby community college library, the Schauerman Library at El Camino College in Torrance, California. Discusses similarities between staff in public and academic libraries; differences between the two environments; and like missions of both…

  13. Future-Proof Your Library

    ERIC Educational Resources Information Center

    Miller, Rebecca

    2008-01-01

    This article presents an excerpt of Library Journal's (LJ's) Movers & Shakers ideas on how to ensure a vital library for the future. Several identify a disconnect between what librarians and libraries do and what users think they do. Mending this gap, they say, would transform library recruitment and library support. While specific insights on…

  14. Public Relations in Special Libraries.

    ERIC Educational Resources Information Center

    Rutkowski, Hollace Ann; And Others

    1991-01-01

    This theme issue includes 11 articles on public relations (PR) in special libraries. Highlights include PR at the Special Libraries Association (SLA); sources for marketing research for libraries; developing a library image; sample PR releases; brand strategies for libraries; case studies; publicizing a consortium; and a bibliography of pertinent…

  15. FCLib: The Feature Characterization Library.

    SciTech Connect

    Gentile, Ann C.; Doyle, Wendy S. K.; Kegelmeyer, W. Philip,; Ulmer, Craig D.

    2008-11-01

    The Feature Characterization Library (FCLib) is a software library that simplifies the process of interrogating, analyzing, and understanding complex data sets generated by finite element applications. This document provides an overview of the library, a description of both the design philosophy and implementation of the library, and examples of how the library can be utilized to extract understanding from raw datasets.

  16. Leadlikeness and structural diversity of synthetic screening libraries.

    PubMed

    Verheij, Herman J

    2006-08-01

    High program failure rates in the pharmaceutical industry have prompted the development of predictive software that can profile compound libraries as being 'druglike' (resembling existing drugs) and/or 'leadlike' (possessing the structural and physicochemical profile of a quality lead). In recent years, these two notions prompted pharmaceutical companies to clean up their corporate libraries of screening compounds. In order to maintain and expand the size and diversity of these corporate libraries, pharmaceutical companies still continue to add compounds to these, mainly by the acquisition of screening libraries. In this paper, we have analyzed 45 commercially available libraries, offered by suppliers of screening chemistry, for leadlikeness and diversity of the offered structures. To this end we have used a set of structural and physicochemical filters for leadlikeness that was developed in-house. These 45 supplier libraries contained a total of 5.3 million structures, of which 49% (2,592,778 structures) turned out to be unique, and only 12% (677,328 structures) were found to be both unique and leadlike. A diversity analysis revealed that big differences exist between the various offered libraries.

  17. ProSAR: a new methodology for combinatorial library design.

    PubMed

    Chen, Hongming; Börjesson, Ulf; Engkvist, Ola; Kogej, Thierry; Svensson, Mats A; Blomberg, Niklas; Weigelt, Dirk; Burrows, Jeremy N; Lange, Tim

    2009-03-01

    A method is introduced for performing reagent selection for chemical library design based on topological (2D) pharmacophore fingerprints. Optimal reagent selection is achieved by optimizing the Shannon entropy of the 2D pharmacophore distribution for the reagent set. The method, termed ProSAR, is therefore expected to enumerate compounds that could serve as a good starting point for deriving a structure activity relationship (SAR) in combinatorial library design. This methodology is exemplified by library design examples where the active compounds were already known. The results show that most of the pharmacophores on the substituents for the active compounds are covered by the designed library. This strategy is further expanded to include product property profiles for aqueous solubility, hERG risk assessment, etc. in the optimization process so that the reagent pharmacophore diversity and the product property profile are optimized simultaneously via a genetic algorithm. This strategy is applied to a two-dimensional library design example and compared with libraries designed by a diversity based strategy which minimizes the average ensemble Tanimoto similarity. Our results show that by using the PSAR methodology, libraries can be designed with simultaneously good pharmacophore coverage and product property profile.

  18. Libraries in Mauritius: Ideal Size for a National Library Service.

    ERIC Educational Resources Information Center

    Harrison, K. C.

    1978-01-01

    A UNESCO consultant describes services provided by academic, public, and school libraries in Mauritius, and discusses levels of professionalism and salaries of librarians, opportunities for library education, and the possibility of developing a national library service. (JAB)

  19. Drug discovery with DNA-encoded chemical libraries.

    PubMed

    Buller, Fabian; Mannocci, Luca; Scheuermann, Jörg; Neri, Dario

    2010-09-15

    DNA-encoded chemical libraries represent a novel avenue for the facile discovery of small molecule ligands against target proteins of biological or pharmaceutical importance. Library members consist of small molecules covalently attached to unique DNA fragments that serve as amplifiable identification barcodes. This encoding allows the in vitro selection of ligands at subpicomolar concentrations from large library populations by affinity capture on a target protein of interest, in analogy to established technologies for the selection of binding polypeptides (e.g., antibodies). Different library formats have been explored by various groups, allowing the construction of chemical libraries comprising up to millions of DNA-encoded compounds. Libraries before and after selection have been characterized by PCR amplification of the DNA codes and subsequent relative quantification of library members using high-throughput sequencing. The most enriched compounds have then been further analyzed in biological assays, in the presence or in the absence of linked DNA. This article reviews experimental strategies used for the construction of DNA-encoded chemical libraries, revealing how selection, decoding, and hit validation technologies have been used for drug discovery programs.

  20. Improving Library Research Skills.

    ERIC Educational Resources Information Center

    Holley, Catherine W.

    This report describes a program to advance library research skills in two sixth grade science classes. The problem was assessed through a survey, questionnaire, and worksheet, and by direct observation. Analysis of probable cause data revealed that students displayed a lack of research skills related to library research. Some of the causes were…

  1. Dumping the "Library."

    ERIC Educational Resources Information Center

    Crowley, Bill

    1998-01-01

    Discusses an alternative to abandoning the word "library" for "information" in graduate education. Recommends patient, consistent effort by library- and information-science educators to convince academic librarians that if they accept the standards of the teaching/research faculty, including the need to earn a Ph.D., it will raise the prestige of…

  2. Global Warming's Library Challenge

    ERIC Educational Resources Information Center

    Meyer, Jennifer

    2008-01-01

    Like every institution that uses energy, consumes resources, and engages in construction or renovation, libraries have an impact on the environment and on the critical problem of climate change. Taking action to protect library collections is not only an idealistic professional goal but also a very practical one. Disaster preparation measures and…

  3. Centennial State Libraries, 1998.

    ERIC Educational Resources Information Center

    Parent, Kathleen D., Ed.

    1998-01-01

    This document consists of 12 consecutive issues of the monthly "Centennial State Libraries" newsletter, of the Colorado Department of Education, State Library and Adult Education Office. The issues cover the year 1998. Each issue of the newsletter--except the August issue which is an Annual Report--includes some or all of the following…

  4. The Amazing Library Computer.

    ERIC Educational Resources Information Center

    Anderson, Eric S.

    1983-01-01

    Identifies computer software designed specifically for library management tasks in three distinct categories: library utility programs, and circulation and catalog programs for floppy disk and for hard disk. Company name and address, program, application, hardware, cost, and comments are provided in each category. (EJS)

  5. Weeding Library Collections.

    ERIC Educational Resources Information Center

    Slote, Stanley J.

    This work, based on two recent research projects in the weeding of library collections and the identification of core collections, provides a comprehensive summary of the literature and research on these topics. It also presents practical guidance in weeding for the professional librarian or for the library school student. The book is divided into…

  6. Small Public Library Management

    ERIC Educational Resources Information Center

    Pearlmutter, Jane; Nelson, Paul

    2012-01-01

    Anyone at the helm of a small public library knows that every little detail counts. But juggling the responsibilities that are part and parcel of the job is far from easy. Finally, here's a handbook that includes everything administrators need to keep a handle on library operations, freeing them up to streamline and improve how the organization…

  7. Merchandising Techniques and Libraries.

    ERIC Educational Resources Information Center

    Green, Sylvie A.

    1981-01-01

    Proposes that libraries employ modern booksellers' merchandising techniques to improve circulation of library materials. Using displays in various ways, the methods and reasons for weeding out books, replacing worn book jackets, and selecting new books are discussed. Suggestions for learning how to market and 11 references are provided. (RBF)

  8. Library Consortia in Hungary

    ERIC Educational Resources Information Center

    Csajbok, Edit; Szluka, Peter; Vasas, Livia

    2012-01-01

    During the last two decades many Hungarian libraries have developed considerably, beyond what was considered possible prior to 1989 and the beginning of events signaling the end of Communism in the country. Some of the modernization of library services has been realized through participation in cooperative agreements. Many smaller and larger…

  9. Guide to Library Automation.

    ERIC Educational Resources Information Center

    Toohill, Barbara G.

    Directed toward librarians and library administrators who wish to procure automated systems or services for their libraries, this guide offers practical suggestions, advice, and methods for determining requirements, estimating costs and benefits, writing specifications procuring systems, negotiating contracts, and installing systems. The advice…

  10. Libraries at the Ready

    ERIC Educational Resources Information Center

    Celano, Donna C.; Neuman, Susan B.

    2016-01-01

    Because English language learners enter kindergarten at a distinct disadvantage, Celano and Neuman examine the role public libraries can play in rallying around these young children to better prepare them for school. The authors document a new program called Every Child Ready to Read, which recently launched in 4,000 public libraries across the…

  11. Privacy and Library Records

    ERIC Educational Resources Information Center

    Bowers, Stacey L.

    2006-01-01

    This paper summarizes the history of privacy as it relates to library records. It commences with a discussion of how the concept of privacy first originated through case law and follows the concept of privacy as it has affected library records through current day and the "USA PATRIOT Act."

  12. Academic Libraries in Japan

    ERIC Educational Resources Information Center

    Cullen, Rowena; Nagata, Haruki

    2008-01-01

    Academic libraries in Japan are well resourced by international standards, and support Japan's internationally recognized research capability well, but there are also ways in which they reflect Japan's strong bureaucratic culture. Recent changes to the status of national university libraries have seen a new interest in customer service, and…

  13. LSCA Builds Michigan Libraries.

    ERIC Educational Resources Information Center

    Michigan Library, Lansing.

    This report highlights 19 of the 48 recently completed public library construction projects in Michigan which received partial funding from the 1983 Emergency Jobs Act. The grants were administered under Title II of the Library Services and Construction Act (LSCA). Introductory material includes listings of the State of Michigan Legislative…

  14. LSCA Builds Michigan Libraries.

    ERIC Educational Resources Information Center

    Michigan Library, Lansing.

    This report highlights 19 of the 48 recently completed public library construction projects in Michigan which received partial funding from the 1983 Emergency Jobs Act. The grants were administered under Title II of the Library Services and Construction Act (LSCA). Introductory material includes listings of the State of Michigan Legislative…

  15. "Greening" up the Library

    ERIC Educational Resources Information Center

    Woodland, Jean

    2010-01-01

    This paper looks at the library's ability to spread environmental conservation efforts throughout the community. The paper suggests various ways library staff can explore environmentally friendly procedures within the context of the media center as well as ways to promote community interest and support. It identifies areas for improvement, ideas…

  16. Library Classification 2020

    ERIC Educational Resources Information Center

    Harris, Christopher

    2013-01-01

    In this article the author explores how a new library classification system might be designed using some aspects of the Dewey Decimal Classification (DDC) and ideas from other systems to create something that works for school libraries in the year 2020. By examining what works well with the Dewey Decimal System, what features should be carried…

  17. Public/Private Libraries.

    ERIC Educational Resources Information Center

    Sapp, Michael J.

    2001-01-01

    Explores how a new school facility can be important, not only as a community center, but also as a resource center for library services such as computer labs, Internet service, and current periodicals. The article also examines how one Missouri school district planned its new school library to serve the community. (GR)

  18. Networking among Chevron Libraries.

    ERIC Educational Resources Information Center

    Linden, Margaret J.

    1989-01-01

    Describes the process by which librarians at the Chevron and Gulf Oil Corporations managed the merger of corporation libraries and developed a framework for a company-wide library network. The discussion covers corporate policies for information exchange, shared resources, and cost control, and examines factors that led to the success of the…

  19. The Depository Library Program.

    ERIC Educational Resources Information Center

    Barrett, William J.

    1979-01-01

    Reviews the history of the federal depository library program, noting the legislation that determined the present system of libraries. Two important developments are described--the format change of the Monthly Catalog and the GPO (Government Printing Office) micropublishing program--and future plans are revealed. (JD)

  20. Libraries at the Ready

    ERIC Educational Resources Information Center

    Celano, Donna C.; Neuman, Susan B.

    2016-01-01

    Because English language learners enter kindergarten at a distinct disadvantage, Celano and Neuman examine the role public libraries can play in rallying around these young children to better prepare them for school. The authors document a new program called Every Child Ready to Read, which recently launched in 4,000 public libraries across the…

  1. "Greening" up the Library

    ERIC Educational Resources Information Center

    Woodland, Jean

    2010-01-01

    This paper looks at the library's ability to spread environmental conservation efforts throughout the community. The paper suggests various ways library staff can explore environmentally friendly procedures within the context of the media center as well as ways to promote community interest and support. It identifies areas for improvement, ideas…

  2. The Animated Library

    ERIC Educational Resources Information Center

    Brewer, Jim; Dyal, Donald H.; Sweet, Robert

    2009-01-01

    Libraries have always been poised at the crossroads of access tools and content. Librarians, their personnel, and supporters have worked for generations to create tools to store and utilize content for the benefit of patrons. Libraries house materials and the tools to unlock them; their staffers teach patrons to use the materials and associated…

  3. Outreach Library Services.

    ERIC Educational Resources Information Center

    The Bookmark, 1985

    1985-01-01

    Focusing on the theme, Outreach Library Services, the articles in this publication provide a panoramic view of outreach services in eight of the public library systems in New York State. The compilation also contains four papers on special topics. Articles included are: (1) "Not So Trivial: In Pursuit of Outreach Services" (Joan F.…

  4. Library Web Site Innovations.

    ERIC Educational Resources Information Center

    Falk, Howard

    1999-01-01

    Reports on some of the new ways public library sites are presenting themselves to their patrons and to the broader World Wide Web audience. Discusses library virtual tours; calendar display; audio-visual materials; resource listings; book clubs; money-raising activities; fugitive fact files; hot item advisors; periodicals; FAQs (frequently asked…

  5. Privacy and Library Records

    ERIC Educational Resources Information Center

    Bowers, Stacey L.

    2006-01-01

    This paper summarizes the history of privacy as it relates to library records. It commences with a discussion of how the concept of privacy first originated through case law and follows the concept of privacy as it has affected library records through current day and the "USA PATRIOT Act."

  6. Guidelines on Library Twinning.

    ERIC Educational Resources Information Center

    Doyle, Robert P., Comp.; Scarry, Patricia, Comp.

    This document serves as an overview of the many forms of library twinning, or formal exchanges of materials and/or staff between two institutions. Twinning can be reciprocal, but often involves a one-way arrangement whereby a library in a developing country receives a visit from a librarian of a developed country. Either way, both institutions can…

  7. Integrated library systems.

    PubMed Central

    Goldstein, C M

    1983-01-01

    The development of integrated library systems is discussed. The four major discussion points are (1) initial efforts; (2) network resources; (3) minicomputer-based systems; and (4) beyond library automation. Four existing systems are cited as examples of current systems. PMID:6354321

  8. Stress in the Library.

    ERIC Educational Resources Information Center

    Bunge, Charles

    1987-01-01

    Reports results of a survey of 800 library staff members on aspects of library work that they find stressful. The findings include sources of satisfaction and stress for all participants, and sources of stress specific to public services librarians, technical services librarians, and support staff members. (CLB)

  9. XML in Libraries.

    ERIC Educational Resources Information Center

    Tennant, Roy, Ed.

    This book presents examples of how libraries are using XML (eXtensible Markup Language) to solve problems, expand services, and improve systems. Part I contains papers on using XML in library catalog records: "Updating MARC Records with XMLMARC" (Kevin S. Clarke, Stanford University) and "Searching and Retrieving XML Records via the…

  10. Revolution and the Library.

    ERIC Educational Resources Information Center

    Gorniak-Kocikowska, Krystyna

    2001-01-01

    Considers the impact that the computer revolution has had on college and university libraries. Discusses the historical background of changes that resulted from the invention of the printing press; the development of national languages; knowledge acquisition; the historical role of religion; content control of libraries; and changes in students.…

  11. The Library as Ecosystem

    ERIC Educational Resources Information Center

    Walter, Scott

    2008-01-01

    Ecology is the study of interactions between organisms and their environment, and the academic library could be considered to be an ecosystem, i.e., a "biological organization" in which multiple species must interact, both with one another and with their environment. The metaphor of the library as ecosystem is flexible enough to be applied not…

  12. Library Instruction Program Proposal.

    ERIC Educational Resources Information Center

    Cassata, Mary B.

    A number of studies cited in the literature show a positive correlation between the students scholastic grade point average and his library usage. The case is made by a growing cult of librarians who are engaged in "teaching the library" that the librarian so engaged makes a direct contribution to the student's success at his studies. Although…

  13. Prison Libraries: Bibliography.

    ERIC Educational Resources Information Center

    Gillespie, David M.

    An Alphabetically arranged bibliography, listing 485 entries representing 518 citations taken from "Poole's Index to Periodical Literature" 1802-1906, "Cannon's Bibliography of Library Economy," and "Library Literature" 1921 to mid-1970. Other sources used include: The Index to the Journal of Correctional Education; ten bibliographies taken from…

  14. Library Connection Development.

    ERIC Educational Resources Information Center

    Berry, John N., III

    1990-01-01

    The John Wiley and Sons publishing company has made a commitment to publishing more tradebooks for the retail and library marketplace. As part of this expansion, Wiley has strengthened its library sales and promotion efforts and launched new publications and promotions to reach librarians. (MES)

  15. Online Library Videos

    ERIC Educational Resources Information Center

    Power, June

    2010-01-01

    One of the challenges of access services is letting patrons know what one has to offer at his or her library, and then communicating how they may avail themselves of those services. Increasingly, libraries are doing this through more than the traditional handouts and newsletters, but also through blogs, Facebook pages, podcasts, and videos. This…

  16. Merchandising Techniques and Libraries.

    ERIC Educational Resources Information Center

    Green, Sylvie A.

    1981-01-01

    Proposes that libraries employ modern booksellers' merchandising techniques to improve circulation of library materials. Using displays in various ways, the methods and reasons for weeding out books, replacing worn book jackets, and selecting new books are discussed. Suggestions for learning how to market and 11 references are provided. (RBF)

  17. Guidelines on Library Twinning.

    ERIC Educational Resources Information Center

    Doyle, Robert P., Comp.; Scarry, Patricia, Comp.

    This document serves as an overview of the many forms of library twinning, or formal exchanges of materials and/or staff between two institutions. Twinning can be reciprocal, but often involves a one-way arrangement whereby a library in a developing country receives a visit from a librarian of a developed country. Either way, both institutions can…

  18. Planning for Library Excellence.

    ERIC Educational Resources Information Center

    Virginia State Library and Archives, Richmond.

    Intended to be used by librarians, this guide will also be useful to boards of trustees, governing officials, members of funding agencies, and community support groups involved in planning on a local level and within the context of regional and state library service. It provides information to help libraries plan and evaluate their services and…

  19. Library Technician Skill Standards.

    ERIC Educational Resources Information Center

    Highline Community Coll., Des Moines, WA.

    This document presents skill standards for library technicians. Introductory sections describe the industry and the job, what skill standards are, how the library technician skill standards were developed, employability skills and critical competencies, and the SCANS (Secretary's Commission on Achieving Necessary Skills) foundation skills profile.…

  20. Iranian Special Library Standards.

    ERIC Educational Resources Information Center

    Harvey, John F.

    The purposes of these standards are: (1) to suggest the steps necessary for the establishment of special libraries; (2) for those recently established, to suggest the steps necessary to achieve satisfactory performance levels in all areas, and finally, (3) for well established libraries, to suggest the steps necessary to achieve excellence. These…

  1. Libraries of the Future.

    ERIC Educational Resources Information Center

    McKenzie, Jamie

    1996-01-01

    Predicts the effects of information technology (IT) on libraries of the future. Discusses negative implications for school libraries. Describes four emerging roles for media specialists: (1) showing students and staff how to navigate information networks; (2) teaching users how to evaluate and select information; (3) designing information systems;…

  2. Image-analysis library

    NASA Technical Reports Server (NTRS)

    1980-01-01

    MATHPAC image-analysis library is collection of general-purpose mathematical and statistical routines and special-purpose data-analysis and pattern-recognition routines for image analysis. MATHPAC library consists of Linear Algebra, Optimization, Statistical-Summary, Densities and Distribution, Regression, and Statistical-Test packages.

  3. The Jimmy Carter Library.

    ERIC Educational Resources Information Center

    Schewe, Donald B.

    1989-01-01

    Reviews past approaches to the preservation of Presidential papers, the development of the system of Presidential Libraries, and the development of the Jimmy Carter Library. The National Archives' approach to computerization to deal with the increasing volume of materials is detailed and the PresNet computerized information system is described.…

  4. XML in Libraries.

    ERIC Educational Resources Information Center

    Tennant, Roy, Ed.

    This book presents examples of how libraries are using XML (eXtensible Markup Language) to solve problems, expand services, and improve systems. Part I contains papers on using XML in library catalog records: "Updating MARC Records with XMLMARC" (Kevin S. Clarke, Stanford University) and "Searching and Retrieving XML Records via the…

  5. Library Media Services Handbook.

    ERIC Educational Resources Information Center

    Winnipeg School Div. Number 1, Manitoba (Canada).

    This 1991 edition of the handbook for Winnipeg School Division Number 1 school library media programs presents detailed program guidelines, objectives, philosophies, and goals in five major sections: (1) Library Policy and Practices (statement of the division's educational philosophy and goals, philosophy and goals of the division's library…

  6. Guidelines for National Libraries.

    ERIC Educational Resources Information Center

    Sylvestre, Guy

    This report is designed to provide practical assistance to government officials and librarians responsible for the planning, creation, and development of national library services. Based on a number of authoritative studies and a broad consensus among experts, including directors of national libraries, these guidelines give special attention to…

  7. Academic Libraries in Iran

    ERIC Educational Resources Information Center

    Deale, H. Vail

    1973-01-01

    Iranian librarianship is in the embryonic stages of development, especially with respect to modern and functional academic libraries. In three major areas--personnel, resources, and physical facilities--the academic libraries are deficient compared with Western standards. (16 references) (Author)

  8. Homelessness in Public Libraries

    ERIC Educational Resources Information Center

    Wong, Yi Ling

    2009-01-01

    This paper takes a theoretical and practical approach in defining the "problem" of homelessness in libraries. The author examines three fundamental problems on homelessness. The three fundamental questions are: (a) Who are the homeless? (b) Why are they homeless? (c) What are their information needs in libraries? These questions are important in…

  9. Libraries, Listservs, and LITA.

    ERIC Educational Resources Information Center

    Williams, Brian

    1992-01-01

    Explains a series of 39 slides used in a presentation covering guides to libraries on the Internet computer network; other INTERNET resources, including bibliographic databases, catalogs, and online services; BITNET servers and LISTSERVS, and the MicroUser's computer conference sponsored by the Library and Information Technology Association…

  10. Global Warming's Library Challenge

    ERIC Educational Resources Information Center

    Meyer, Jennifer

    2008-01-01

    Like every institution that uses energy, consumes resources, and engages in construction or renovation, libraries have an impact on the environment and on the critical problem of climate change. Taking action to protect library collections is not only an idealistic professional goal but also a very practical one. Disaster preparation measures and…

  11. Dumping the "Library."

    ERIC Educational Resources Information Center

    Crowley, Bill

    1998-01-01

    Discusses an alternative to abandoning the word "library" for "information" in graduate education. Recommends patient, consistent effort by library- and information-science educators to convince academic librarians that if they accept the standards of the teaching/research faculty, including the need to earn a Ph.D., it will raise the prestige of…

  12. Library Technology International

    ERIC Educational Resources Information Center

    Breeding, Marshall

    2008-01-01

    The author has been extremely fortunate over the last few years to have had the opportunity to travel to many different parts of the world and speak and work with librarians in many countries and to have the chance to see first-hand some incredible libraries that demonstrate creative approaches to library services, innovative uses of technology,…

  13. Library Technology International

    ERIC Educational Resources Information Center

    Breeding, Marshall

    2008-01-01

    The author has been extremely fortunate over the last few years to have had the opportunity to travel to many different parts of the world and speak and work with librarians in many countries and to have the chance to see first-hand some incredible libraries that demonstrate creative approaches to library services, innovative uses of technology,…

  14. Redefining Services to Libraries.

    ERIC Educational Resources Information Center

    Hearty, John; Smith, Robert

    1993-01-01

    Describes the strategic plan developed for reference services offered by OCLC Online Computer Library Center to provide easier access to, and use of, information and knowledge. Topics addressed include the environment of libraries and publishers, including budgets, networks, and pricing, and future plans, including an emphasis on online products.…

  15. Financing Public Library Construction.

    ERIC Educational Resources Information Center

    Rohlf, Robert H.; Stoffel, Lester L.

    1987-01-01

    Reviews financing options available to Illinois public libraries for construction or expansion, including general obligation bonds, mortgage funds, building reserve funds, building fund levies, lease back arrangements, sale of air or ground development rights, interest on special funds, gift funds and grants, Library Service and Construction Act…

  16. Library Media Services Handbook.

    ERIC Educational Resources Information Center

    Winnipeg School Div. Number 1, Manitoba (Canada).

    This 1991 edition of the handbook for Winnipeg School Division Number 1 school library media programs presents detailed program guidelines, objectives, philosophies, and goals in five major sections: (1) Library Policy and Practices (statement of the division's educational philosophy and goals, philosophy and goals of the division's library…

  17. Small Public Library Management

    ERIC Educational Resources Information Center

    Pearlmutter, Jane; Nelson, Paul

    2012-01-01

    Anyone at the helm of a small public library knows that every little detail counts. But juggling the responsibilities that are part and parcel of the job is far from easy. Finally, here's a handbook that includes everything administrators need to keep a handle on library operations, freeing them up to streamline and improve how the organization…

  18. Building a Library Intranet.

    ERIC Educational Resources Information Center

    Davis, Marc; Boyer, Janice

    "Intranets"--web sites written and used internally by organizations--are being developed as a means of enhancing communication, improving productivity, and reducing costs. The University Library at the University of Nebraska at Omaha is in the early stages of developing an Intranet. Considerations that led the library to establish an…

  19. Stress in the Library.

    ERIC Educational Resources Information Center

    Bunge, Charles

    1987-01-01

    Reports results of a survey of 800 library staff members on aspects of library work that they find stressful. The findings include sources of satisfaction and stress for all participants, and sources of stress specific to public services librarians, technical services librarians, and support staff members. (CLB)

  20. The Jimmy Carter Library.

    ERIC Educational Resources Information Center

    Schewe, Donald B.

    1989-01-01

    Reviews past approaches to the preservation of Presidential papers, the development of the system of Presidential Libraries, and the development of the Jimmy Carter Library. The National Archives' approach to computerization to deal with the increasing volume of materials is detailed and the PresNet computerized information system is described.…

  1. The Animated Library

    ERIC Educational Resources Information Center

    Brewer, Jim; Dyal, Donald H.; Sweet, Robert

    2009-01-01

    Libraries have always been poised at the crossroads of access tools and content. Librarians, their personnel, and supporters have worked for generations to create tools to store and utilize content for the benefit of patrons. Libraries house materials and the tools to unlock them; their staffers teach patrons to use the materials and associated…

  2. Homelessness in Public Libraries

    ERIC Educational Resources Information Center

    Wong, Yi Ling

    2009-01-01

    This paper takes a theoretical and practical approach in defining the "problem" of homelessness in libraries. The author examines three fundamental problems on homelessness. The three fundamental questions are: (a) Who are the homeless? (b) Why are they homeless? (c) What are their information needs in libraries? These questions are important in…

  3. Availability Studies in Libraries.

    ERIC Educational Resources Information Center

    Mansbridge, John

    1986-01-01

    Examines library availability studies for the past 50 years as a measure of library effectiveness and looks at their differing sources of study samples, methods for gathering data, categories of nonavailability, and data analysis. The Kantor branching technique developed in 1976 is described as the standard analysis method. (Author/EM)

  4. Mechanical Systems and Libraries.

    ERIC Educational Resources Information Center

    Dubin, Fred

    1987-01-01

    Discusses the following aspects of the design of mechanical and electrical systems to meet the various requirements of libraries: (1) library planning teams; (2) raised floors; (3) lighting considerations; (4) air quality; (5) acoustics; and (6) climate controls. The importance of adaptability to meet future needs is stressed. (MES)

  5. Library Laws of Texas.

    ERIC Educational Resources Information Center

    Seidenberg, Ed, Ed.

    Compiled to provide a central reference point for all legislative information pertaining to libraries in the state of Texas, this publication includes all pertinent legislation as amended through the 66th Legislature, Regular Session, 1979. It contains articles dealing specifically with archives, buildings and property, city libraries, non-profit…

  6. Library Connection Development.

    ERIC Educational Resources Information Center

    Berry, John N., III

    1990-01-01

    The John Wiley and Sons publishing company has made a commitment to publishing more tradebooks for the retail and library marketplace. As part of this expansion, Wiley has strengthened its library sales and promotion efforts and launched new publications and promotions to reach librarians. (MES)

  7. Budgeting for Libraries.

    ERIC Educational Resources Information Center

    Randall, G. E.

    Empirically and rationally derived bases for determining the costs for industrial libraries are suggested. Taken into consideration is the fact that recent accounting procedures and the advent of new technologies have introduced costs into the library budget so that literature and personnel costs may now account for only 75-80 percent of the…

  8. Trotsky's Vision of Libraries.

    ERIC Educational Resources Information Center

    Baker, William; Hurych, Jitka

    1991-01-01

    Discusses Leon Trotsky's views on libraries, librarians, and librarianship in Soviet society in the 1920s as expressed in a speech, "Leninism and Library Work." Topics discussed include role of librarian in promoting literacy, including the use of maps and reference books to explain newspaper stories; the selection of books; and fighting…

  9. An Online Library Catalogue.

    ERIC Educational Resources Information Center

    Alloro, Giovanna; Ugolini, Donatella

    1992-01-01

    Describes the implementation of an online catalog in the library of the National Institute for Cancer Research and the Clinical and Experimental Oncology Institute of the University of Genoa. Topics addressed include automation of various library functions, software features, database management, training, and user response. (10 references) (MES)

  10. Disaster Planning in Libraries

    ERIC Educational Resources Information Center

    Wong, Yi Ling; Green, Ravonne

    2006-01-01

    Disaster preparedness is an important issue in library management today. This article presents a general overview of the theoretical aspects of disaster planning in libraries. The stages of disaster planning are a circular process of planning, prevention, response, recovery, preparedness, and training.

  11. Online Library Videos

    ERIC Educational Resources Information Center

    Power, June

    2010-01-01

    One of the challenges of access services is letting patrons know what one has to offer at his or her library, and then communicating how they may avail themselves of those services. Increasingly, libraries are doing this through more than the traditional handouts and newsletters, but also through blogs, Facebook pages, podcasts, and videos. This…

  12. Library Consortia in Hungary

    ERIC Educational Resources Information Center

    Csajbok, Edit; Szluka, Peter; Vasas, Livia

    2012-01-01

    During the last two decades many Hungarian libraries have developed considerably, beyond what was considered possible prior to 1989 and the beginning of events signaling the end of Communism in the country. Some of the modernization of library services has been realized through participation in cooperative agreements. Many smaller and larger…

  13. Disaster Planning in Libraries

    ERIC Educational Resources Information Center

    Wong, Yi Ling; Green, Ravonne

    2006-01-01

    Disaster preparedness is an important issue in library management today. This article presents a general overview of the theoretical aspects of disaster planning in libraries. The stages of disaster planning are a circular process of planning, prevention, response, recovery, preparedness, and training.

  14. The Amazing Library Computer.

    ERIC Educational Resources Information Center

    Anderson, Eric S.

    1983-01-01

    Identifies computer software designed specifically for library management tasks in three distinct categories: library utility programs, and circulation and catalog programs for floppy disk and for hard disk. Company name and address, program, application, hardware, cost, and comments are provided in each category. (EJS)

  15. Revolution and the Library.

    ERIC Educational Resources Information Center

    Gorniak-Kocikowska, Krystyna

    2001-01-01

    Considers the impact that the computer revolution has had on college and university libraries. Discusses the historical background of changes that resulted from the invention of the printing press; the development of national languages; knowledge acquisition; the historical role of religion; content control of libraries; and changes in students.…

  16. Corporations and Library Fundraising.

    ERIC Educational Resources Information Center

    DiMattia, Susan S.

    1984-01-01

    Examination of corporate donations of cash, products, service, and expertise to libraries highlights industry contributions in 1980; why corporations give; examples of corporate donations to various libraries (Brooklyn Public, New York Public, Altoona Area Public, Boston Public); planning fund-raising compaigns; and seven strategic planning…

  17. Photocopying by Corporate Libraries.

    ERIC Educational Resources Information Center

    Association of American Publishers, New York, NY.

    This document consists of a summary discussion of the relevant sections of the new copyright law--Section 107, fair use, and Section 108, reproduction by libraries and archives--supplementary guidelines for corporate libraries developed by the Association of American Publishers (AAP) and the Authors League, and some of the more frequently asked…

  18. Libraries and Lenin.

    ERIC Educational Resources Information Center

    Lynn, Karen

    This instructional unit combines a study of the Soviet leader V. I. Lenin with a study of libraries. Lenin was selected as the focus because of his support of books and libraries and because he oversaw a revolution that altered the political and social structure of Russia and the balance of power throughout the world. Included are lesson plan…

  19. Literacy Projects in Libraries.

    ERIC Educational Resources Information Center

    Gaughan, Karen K.

    1986-01-01

    Literacy Volunteers of America is described as a grassroots effort that has grown to national proportions. An overview of its development and case studies of library literacy projects in various states are provided, and recommendations are made for continued and future library participation in the literacy effort. (EM)

  20. Academic Libraries in Japan

    ERIC Educational Resources Information Center

    Cullen, Rowena; Nagata, Haruki

    2008-01-01

    Academic libraries in Japan are well resourced by international standards, and support Japan's internationally recognized research capability well, but there are also ways in which they reflect Japan's strong bureaucratic culture. Recent changes to the status of national university libraries have seen a new interest in customer service, and…

  1. The Undergraduate Library Collection.

    ERIC Educational Resources Information Center

    Stewart, Rolland C.

    The development of undergraduate library collections is shown under two aspects: (1) the formation of the basic collection of the Undergraduate Library of the University of Michigan, and (2) the problems, practical and theoretial, encountered in the day-to-day effort to maintain the collection. The budget is the sire of all selection criteria.…

  2. The Library as Ecosystem

    ERIC Educational Resources Information Center

    Walter, Scott

    2008-01-01

    Ecology is the study of interactions between organisms and their environment, and the academic library could be considered to be an ecosystem, i.e., a "biological organization" in which multiple species must interact, both with one another and with their environment. The metaphor of the library as ecosystem is flexible enough to be applied not…

  3. Library Reference Services.

    ERIC Educational Resources Information Center

    Miller, Constance; And Others

    1985-01-01

    Seven articles on library reference services highlight reference obsolescence in academic libraries, major studies of unobtrusive reference tests, methods for evaluating reference desk performance, reference interview evaluation, problems of reference desk control, online searching by end users, and reference collection development in…

  4. Fermilab Library projects

    SciTech Connect

    Garrett, P.; Ritchie, D.

    1990-05-03

    Preprint database management as done at various centers -- the subject of this workshop -- is hard to separate from the overall activities of the particular center. We therefore present the wider context at the Fermilab Library into which preprint database management fits. The day-to-day activities of the Library aside, the dominant activity at present is that of the ongoing Fermilab Library Automation. A less dominant but relatively time-consuming activity is that of doing more online searches in commercial databases on behalf of laboratory staff and visitors. A related activity is that of exploring the benefits of end-user searching of similar sources as opposed to library staff searching of the same. The Library Automation Project, which began about two years ago, is about to go fully online.'' The rationale behind this project is described in the documents developed during the December 1988--February 1989 planning phase.

  5. Marketing and health libraries.

    PubMed

    Wakeham, Maurice

    2004-12-01

    To present an overview of the concepts of marketing and to examine ways in which they can be applied to health libraries. A review was carried out of literature relating to health libraries using LISA, CINAHL, BNI and Google. Marketing is seen as a strategic management activity aimed at developing customer relationships. Concepts such as the 'four Ps' (product, price, place and promotion), marketing plans, the marketing mix, segmentation, promotion and evaluation are identified and discussed in relation to health libraries. In increasingly complex health service and information environments, the marketing and promotion of library services is becoming more important if those services are to justify the resources given to them. Marketing techniques are equally applicable to physical and digital library services.

  6. Be a School Library Advocate

    ERIC Educational Resources Information Center

    Schuckett, Sandy

    2005-01-01

    The brief history and background of the Library Association that sponsored the National Library Legislative Day in Washington is outlined. The specific issues, such as ESEA, the Library Services and Technology Act (LSTA), Copyright, and E-Rate, are discussed.

  7. Academic Library Consortia in Transition.

    ERIC Educational Resources Information Center

    Alberico, Ralph

    2002-01-01

    Using the example of the Virtual Library of Virginia, describes how library consortia are in a state of transformation as technology enables the development of virtual libraries while expanding opportunities for sharing printed works. (EV)

  8. Essentials of Library Manpower Budgeting

    ERIC Educational Resources Information Center

    Fairholm, Gilbert W.

    1970-01-01

    The State University of New York has prepared a library manpower budget formula for its several campuses by developing weighted standard times for accomplishing library operations in various kinds of institutions correlated with various library characteristics. (Author/NH)

  9. Academic Library Consortia in Transition.

    ERIC Educational Resources Information Center

    Alberico, Ralph

    2002-01-01

    Using the example of the Virtual Library of Virginia, describes how library consortia are in a state of transformation as technology enables the development of virtual libraries while expanding opportunities for sharing printed works. (EV)

  10. EPA Library Network Communication Strategies

    EPA Pesticide Factsheets

    To establish Agency-wide procedures for the EPA National Library Network libraries to communicate, using a range of established mechanisms, with other EPA libraries, EPA staff, organizations and the public.

  11. The Computer as Library Aide.

    ERIC Educational Resources Information Center

    Truett, Carol

    1983-01-01

    Discusses use of computer programs in handling such library tasks as cataloging, inventory, and circulation. Reviews several programs and provides a listing of available library software. These include library catalog programs, circulation/overdues programs, and inventory control. (JN)

  12. Library Service to College Students

    ERIC Educational Resources Information Center

    Veit, Fritz

    1976-01-01

    Analyzes major factors which have had an impact on library services to college undergraduates: student body, collections, teaching methods and philosophies, cooperative programs, hours of service, user services, library instruction, and special library units. (LS)

  13. Fundamentals of Library Science. Library Science 424.

    ERIC Educational Resources Information Center

    Foster, Donald L.

    An introductory letter, a list of general instructions on how to proceed with a correspondence course, a syllabus, and an examination request form are presented for a correspondence course in the fundamentals of library science offered by the University of New Mexico's Division of Continuing Education and Community Services. The course is a survey…

  14. Fundamentals of Library Science. Library Science 424.

    ERIC Educational Resources Information Center

    Foster, Donald L.

    An introductory letter, a list of general instructions on how to proceed with a correspondence course, a syllabus, and an examination request form are presented for a correspondence course in the fundamentals of library science offered by the University of New Mexico's Division of Continuing Education and Community Services. The course is a survey…

  15. Library Buildings 2009: The Constant Library

    ERIC Educational Resources Information Center

    Fox, Bette-Lee

    2009-01-01

    Can it be only two years, as Alan Jay Lerner once wrote, "since the whole [economic] rigmarole began"? Yet libraries have weathered to varying degrees the unreliability of funding, especially with regard to programming, materials, and hours. Money earmarked years ago is seeing construction through to conclusion; state support has helped out in…

  16. Encoded libraries of chemically modified peptides.

    PubMed

    Heinis, Christian; Winter, Greg

    2015-06-01

    The use of powerful technologies for generating and screening DNA-encoded protein libraries has helped drive the development of proteins as pharmaceutical ligands. However the development of peptides as pharmaceutical ligands has been more limited. Although encoded peptide libraries are typically several orders of magnitude larger than classical chemical libraries, can be more readily screened, and can give rise to higher affinity ligands, their use as pharmaceutical ligands is limited by their intrinsic properties. Two of the intrinsic limitations include the rotational flexibility of the peptide backbone and the limited number (20) of natural amino acids. However these limitations can be overcome by use of chemical modification. For example, the libraries can be modified to introduce topological constraints such as cyclization linkers, or to introduce new chemical entities such as small molecule ligands, fluorophores and photo-switchable compounds. This article reviews the chemistry involved, the properties of the peptide ligands, and the new opportunities offered by chemical modification of DNA-encoded peptide libraries.

  17. Probing chemical space with alkaloid-inspired libraries

    NASA Astrophysics Data System (ADS)

    McLeod, Michael C.; Singh, Gurpreet; Plampin, James N.; Rane, Digamber; Wang, Jenna L.; Day, Victor W.; Aubé, Jeffrey

    2014-02-01

    Screening of small-molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries because of their structural complexity and sp3-rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp3 content, comparable to a basis set of representative natural products and were highly rule-of-five compliant.

  18. Probing chemical space with alkaloid-inspired libraries.

    PubMed

    McLeod, Michael C; Singh, Gurpreet; Plampin, James N; Rane, Digamber; Wang, Jenna L; Day, Victor W; Aubé, Jeffrey

    2014-02-01

    Screening of small-molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries because of their structural complexity and sp(3)-rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp(3) content, comparable to a basis set of representative natural products and were highly rule-of-five compliant.

  19. Revised Extended Grid Library

    SciTech Connect

    Martz, Roger L.

    2016-07-15

    The Revised Eolus Grid Library (REGL) is a mesh-tracking library that was developed for use with the MCNP6TM computer code so that (radiation) particles can track on an unstructured mesh. The unstructured mesh is a finite element representation of any geometric solid model created with a state-of-the-art CAE/CAD tool. The mesh-tracking library is written using modern Fortran and programming standards; the library is Fortran 2003 compliant. The library was created with a defined application programmer interface (API) so that it could easily integrate with other particle tracking/transport codes. The library does not handle parallel processing via the message passing interface (mpi), but has been used successfully where the host code handles the mpi calls. The library is thread-safe and supports the OpenMP paradigm. As a library, all features are available through the API and overall a tight coupling between it and the host code is required. Features of the library are summarized with the following list: • can accommodate first and second order 4, 5, and 6-sided polyhedra • any combination of element types may appear in a single geometry model • parts may not contain tetrahedra mixed with other element types • pentahedra and hexahedra can be together in the same part • robust handling of overlaps and gaps • tracks element-to-element to produce path length results at the element level • finds element numbers for a given mesh location • finds intersection points on element faces for the particle tracks • produce a data file for post processing results analysis • reads Abaqus .inp input (ASCII) files to obtain information for the global mesh-model • supports parallel input processing via mpi • support parallel particle transport by both mpi and OpenMP

  20. Marketing the hospital library.

    PubMed

    Bridges, Jane

    2005-01-01

    Many librarians do not see themselves as marketers, but marketing is an essential role for hospital librarians. Library work involves education, and there are parallels between marketing and education as described in this article. It is incumbent upon hospital librarians actively to pursue ways of reminding their customers about library services. This article reinforces the idea that marketing is an element in many of the things that librarians already do, and includes a list of suggested marketing strategies intended to remind administrators, physicians, and other customers that they have libraries in their organizations.

  1. Development of a large peptoid–DOTA combinatorial library

    PubMed Central

    Singh, Jaspal; Lopes, Daniel

    2016-01-01

    Abstract Conventional one‐bead one‐compound (OBOC) library synthesis is typically used to identify molecules with therapeutic value. The design and synthesis of OBOC libraries that contain molecules with imaging or even potentially therapeutic and diagnostic capacities (e.g. theranostic agents) has been overlooked. The development of a therapeutically active molecule with a built‐in imaging component for a certain target is a daunting task, and structure‐based rational design might not be the best approach. We hypothesize to develop a combinatorial library with potentially therapeutic and imaging components fused together in each molecule. Such molecules in the library can be used to screen, identify, and validate as direct theranostic candidates against targets of interest. As the first step in achieving that aim, we developed an on‐bead library of 153,600 Peptoid–DOTA compounds in which the peptoids are the target‐recognizing and potentially therapeutic components and the DOTA is the imaging component. We attached the DOTA scaffold to TentaGel beads using one of the four arms of DOTA, and we built a diversified 6‐mer peptoid library on the remaining three arms. We evaluated both the synthesis and the mass spectrometric sequencing capacities of the test compounds and of the final library. The compounds displayed unique ionization patterns including direct breakages of the DOTA scaffold into two units, allowing clear decoding of the sequences. Our approach provides a facile synthesis method for the complete on‐bead development of large peptidomimetic–DOTA libraries for screening against biological targets for the identification of potential theranostic agents in the future. © 2016 The Authors. Biopolymers Published by Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 673–684, 2016. PMID:27257968

  2. DNA-encoded chemical libraries: foundations and applications in lead discovery.

    PubMed

    Zimmermann, Gunther; Neri, Dario

    2016-11-01

    DNA-encoded chemical libraries have emerged as a powerful tool for hit identification in the pharmaceutical industry and in academia. Similar to biological display techniques (such as phage display technology), DNA-encoded chemical libraries contain a link between the displayed chemical building block and an amplifiable genetic barcode on DNA. Using routine procedures, libraries containing millions to billions of compounds can be easily produced within a few weeks. The resulting compound libraries are screened in a single test tube against proteins of pharmaceutical interest and hits can be identified by PCR amplification of DNA barcodes and subsequent high-throughput sequencing.

  3. Whitmore Library: A New Concept of Public Library Services.

    ERIC Educational Resources Information Center

    Schuurman, Guy

    Until 1972, library services in Salt Lake County consisted of a group of branch libraries with nearly identical collections for recreational reading. Because the needs of the community had become more complex, a new regional library was built to coordinate library operations and establish new services. Among the innovations in public library…

  4. Library Statistics Program: State Library Agency Report for FY 2006

    ERIC Educational Resources Information Center

    Institute of Museum and Library Services, 2007

    2007-01-01

    This report marks the first release of library statistics data from the Institute of Museum and Library Services. It contains data on state library agencies in the 50 states and the District of Columbia for state fiscal year (FY) 2006. The data were collected through the State Library Agencies (StLA) Survey, the product of a cooperative effort…

  5. Library Webmasters in Medium-Sized Academic Libraries

    ERIC Educational Resources Information Center

    Kneip, Jason

    2007-01-01

    Library webmasters in medium-sized academic libraries were surveyed about their educational backgrounds, job responsibilities, and training and experience levels in Web development. The article summarizes the findings of the survey with recommendations for libraries and library and information science programs. (Contains 7 tables, 5 figures,and 5…

  6. Brown County Library: Library of the Year 1994.

    ERIC Educational Resources Information Center

    Berry, John

    1994-01-01

    Describes the management, programs, and services at the Brown County Library (Wisconsin), winner of the Library of the Year award sponsored by Gale Research Inc, and "Library Journal." Highlights include involvement of library staff; financial support; total quality management; coalitions with local businesses, community agencies, and…

  7. Redwood City Public Library: Library of the Year 1992.

    ERIC Educational Resources Information Center

    Berry, John

    1992-01-01

    Describes programs at the Redwood City Public Library (California), winner of the Library of the Year Award from Gale Research Inc. and "Library Journal." Highlights include a newly renovated building; a mission statement that reflects the library's role; staff development; increases in circulation and reference; children's services; and…

  8. National Libraries Section. General Research Libraries Division. Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    Papers on national library services and activities, which were presented at the 1983 International Federation of Library Associations (IFLA) conference, include: (1) "The National Library of China in its Gradual Application of Modern Technology," a discussion by Zhu Nan and Zhu Yan (China) of microform usage and library automation; (2)…

  9. National Libraries Section. General Research Libraries Division. Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    Papers on national library services and activities, which were presented at the 1983 International Federation of Library Associations (IFLA) conference, include: (1) "The National Library of China in its Gradual Application of Modern Technology," a discussion by Zhu Nan and Zhu Yan (China) of microform usage and library automation; (2)…

  10. 2010 Library of the Year: Columbus Metropolitan Library

    ERIC Educational Resources Information Center

    Berry, John N., III

    2010-01-01

    This article features Columbus Metropolitan Library (CML), winner of the Gale/"Library Journal" Library of the Year Award 2010. CML, comprised of an operations center and 21 branches, serves the 847,376 people who inhabit a large portion of Franklin County in central Ohio. It is an independent library with its own taxing district. CML…

  11. The USF Libraries Virtual Library Project: A Blueprint for Development.

    ERIC Educational Resources Information Center

    Metz-Wiseman, Monica; Silver, Susan; Hanson, Ardis; Johnston, Judy; Grohs, Kim; Neville, Tina; Sanchez, Ed; Gray, Carolyn

    This report of the Virtual Library Planning Committee (VLPC) is intending to serve as a blueprint for the University of South Florida (USF) Libraries as it shifts from print to digital formats in its evolution into a "Virtual Library". A comprehensive planning process is essential for the USF Libraries to make optimum use of technology,…

  12. Public Libraries Section. Libraries Serving General Public Division. Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    Papers on public libraries, which were presented at the 1983 International Federation of Library Associations (IFLA) conference, include: (1) "The Role of Public Libraries in Developing Countries with Particular Reference to the Gambia" by Sally P. C. N'Jie (The Gambia); (2) "Public Libraries in the Federal Republic of Germany…

  13. Public Libraries Section. Libraries Serving General Public Division. Papers.

    ERIC Educational Resources Information Center

    International Federation of Library Associations, The Hague (Netherlands).

    Papers on public libraries, which were presented at the 1983 International Federation of Library Associations (IFLA) conference, include: (1) "The Role of Public Libraries in Developing Countries with Particular Reference to the Gambia" by Sally P. C. N'Jie (The Gambia); (2) "Public Libraries in the Federal Republic of Germany…

  14. Polybenzimidazole compounds

    DOEpatents

    Klaehn, John R.; Peterson, Eric S.; Wertsching, Alan K.; Orme, Christopher J.; Luther, Thomas A.; Jones, Michael G.

    2010-08-10

    A PBI compound that includes imidazole nitrogens, at least a portion of which are substituted with an organic-inorganic hybrid moiety. At least 85% of the imidazole nitrogens may be substituted. The organic-inorganic hybrid moiety may be an organosilane moiety, for example, (R)Me.sub.2SiCH.sub.2--, where R is selected from among methyl, phenyl, vinyl, and allyl. The PBI compound may exhibit similar thermal properties in comparison to the unsubstituted PBI. The PBI compound may exhibit a solubility in an organic solvent greater than the solubility of the unsubstituted PBI. The PBI compound may be included in separatory media. A substituted PBI synthesis method may include providing a parent PBI in a less than 5 wt % solvent solution. Substituting may occur at about room temperature and/or at about atmospheric pressure. Substituting may use at least five equivalents in relation to the imidazole nitrogens to be substituted or, preferably, about fifteen equivalents.

  15. Polybenzimidazole compounds

    SciTech Connect

    Klaehn, John R; Peterson, Eric S; Orme, Christopher J; Jones, Michael G; Wertsching, Alan K; Luther, Thomas A; Trowbridge, Tammy L

    2011-11-22

    A PBI compound includes imidazole nitrogens at least a portion of which are substituted with a moiety containing a carbonyl group, the substituted imidazole nitrogens being bonded to carbon of the carbonyl group. At least 85% of the nitrogens may be substituted. The carbonyl-containing moiety may include RCO--, where R is alkoxy or haloalkyl. The PBI compound may exhibit a first temperature marking an onset of weight loss corresponding to reversion of the substituted PBI that is less than a second temperature marking an onset of decomposition of an otherwise identical PBI compound without the substituted moiety. The PBI compound may be included in separatory media. A substituted PBI synthesis method may include providing a parent PBI in a less than 5 wt % solvent solution. Substituting may use more than 5 equivalents in relation to the imidazole nitrogens to be substituted.

  16. Optimization of focused chemical libraries using recursive partitioning.

    PubMed

    Rusinko, Andrew; Young, S Stanley; Drewry, David H; Gerritz, Sam W

    2002-03-01

    A number of methods currently exist for designing chemical libraries. General or universal libraries use a measurement of chemical diversity in their design and seek to cover as much of chemical space as possible in order to maximize the likelihood of discovering a novel lead class of active compounds. Focused chemical libraries are then synthesized to expand on this particular class and thoroughly explore the space about it. Rarely, however, is relevant biological data tightly incorporated in the design of focused libraries. Recursive partitioning is a statistical technique that is used to quickly build SAR models from high-throughput screening data sets and associated chemical descriptors. Using these models in a virtual screening mode significantly increases the probability of finding other active compounds. The predicted activity can be also be used as the fitness function for a genetic algorithm that is designed to select monomer subsets having a higher probability of being active. This dramatically reduces the number of compounds that need to be synthesized in focused libraries thus saving considerable time, effort and expense. This paper describes how recursive partitioning models are used to optimize the design of focused chemical libraries.

  17. Composition and applications of focus libraries to phenotypic assays.

    PubMed

    Wassermann, Anne Mai; Camargo, Luiz M; Auld, Douglas S

    2014-01-01

    The wealth of bioactivity information now available on low-molecular weight compounds has enabled a paradigm shift in chemical biology and early phase drug discovery efforts. Traditionally chemical libraries have been most commonly employed in screening approaches where a bioassay is used to characterize a chemical library in a random search for active samples. However, robust curating of bioassay data, establishment of ontologies enabling mining of large chemical biology datasets, and a wealth of public chemical biology information has made possible the establishment of highly annotated compound collections. Such annotated chemical libraries can now be used to build a pathway/target hypothesis and have led to a new view where chemical libraries are used to characterize a bioassay. In this article we discuss the types of compounds in these annotated libraries composed of tools, probes, and drugs. As well, we provide rationale and a few examples for how such libraries can enable phenotypic/forward chemical genomic approaches. As with any approach, there are several pitfalls that need to be considered and we also outline some strategies to avoid these.

  18. Composition and applications of focus libraries to phenotypic assays

    PubMed Central

    Wassermann, Anne Mai; Camargo, Luiz M.; Auld, Douglas S.

    2014-01-01

    The wealth of bioactivity information now available on low-molecular weight compounds has enabled a paradigm shift in chemical biology and early phase drug discovery efforts. Traditionally chemical libraries have been most commonly employed in screening approaches where a bioassay is used to characterize a chemical library in a random search for active samples. However, robust curating of bioassay data, establishment of ontologies enabling mining of large chemical biology datasets, and a wealth of public chemical biology information has made possible the establishment of highly annotated compound collections. Such annotated chemical libraries can now be used to build a pathway/target hypothesis and have led to a new view where chemical libraries are used to characterize a bioassay. In this article we discuss the types of compounds in these annotated libraries composed of tools, probes, and drugs. As well, we provide rationale and a few examples for how such libraries can enable phenotypic/forward chemical genomic approaches. As with any approach, there are several pitfalls that need to be considered and we also outline some strategies to avoid these. PMID:25104937

  19. Organic Contaminants Library for the Sample Analysis at Mars

    NASA Astrophysics Data System (ADS)

    Misra, P.; Garcia-Sanchez, R.; Canham, J.; Mahaffy, P. R.

    2012-12-01

    A library containing mass spectra for Sample Analysis at Mars (SAM) materials has been developed with the purpose of contamination identification and control. Based on analysis of the Gas Chromatography-Mass Spectrometric (GCMS) data through thermal desorption, organic compounds were successfully identified from material samples, such as polymers, paints and adhesives. The library contains the spectra for all the compounds found in each of these analyzed files and is supplemented by a file information spreadsheet, a spreadsheet-formatted library for easy searching, and a Perfluorotributylamine (PFTBA) based normalization protocol to make corrections to SAM data in order to meet the standard set by commercial libraries. An example of the library in use can be seen in Figure 1, where the abundances match closely, the spectral shape is retained, and the library picks up on it with an 88% identification probability. Of course, there are also compounds that have not been identified and are retained as unknowns. The library we have developed, along with its supplemental materials, is useful from both organizational and practical viewpoints. Through them we are able to organize large volumes of GCMS data, while at the same time breaking down the components that each material sample is made of. This approach in turn allows us straightforward and fast access to information that will be critical while performing analysis on the data recorded by the SAM instrumentation. In addition, the normalization protocol dramatically increased the identification probability. In SAM GCMS, PFTBA signals were obfuscated, resulting in library matches far away from PFTBA; by using the normalization protocol we were able to transform it into a 92% probable spectral match for PFTBA. The project has demonstrated conclusively that the library is successful in identifying unknown compounds utilizing both the Automated Mass Spectral Deconvolution & Identification System (AMDIS) and the Ion

  20. Controlling hospital library theft

    PubMed Central

    Cuddy, Theresa M.; Marchok, Catherine

    2003-01-01

    At Capital Health System/Fuld Campus (formerly Helene Fuld Medical Center), the Health Sciences Library lost many books and videocassettes. These materials were listed in the catalog but were missing when staff went to the shelves. The hospital had experienced a downsizing of staff, a reorganization, and a merger. When the library staff did an inventory, $10,000 worth of materials were found to be missing. We corrected the situation through a series of steps that we believe will help other libraries control their theft. Through regularly scheduling inventories, monitoring items, advertising, and using specific security measures, we have successfully controlled the library theft. The January 2002 inventory resulted in meeting our goal of zero missing books and videocassettes. We work to maintain that goal. PMID:12883573