Science.gov

Sample records for 11c-labelled compound libraries

  1. 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.

  2. 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/

  3. Synthesis of (11)C-labeled retinoic acid, [(11)C]ATRA, via an alkenylboron precursor by Pd(0)-mediated rapid C-[(11)C]methylation.

    PubMed

    Suzuki, Masaaki; Takashima-Hirano, Misato; Ishii, Hideki; Watanabe, Chika; Sumi, Kengo; Koyama, Hiroko; Doi, Hisashi

    2014-08-01

    Retinoids are a class of chemical compounds which include both natural dietary vitamin A (retinol) metabolites and active synthetic analogs. Both experimental and clinical studies have revealed that retinoids regulate a wide variety of essential biological processes. In this study, we synthesized (11)C-labeled all-trans-retinoic acid (ATRA), the most potent biologically active metabolite of retinol and used in the treatment of acute promyelocytic leukemia. The synthesis of (11)C-labeled ATRA was accomplished by a combination of rapid Pd(0)-mediated C-[(11)C]methylation of the corresponding pinacol borate precursor prepared by 8 steps and hydrolysis. [(11)C]ATRA will prove useful as a PET imaging agent, particularly for elucidating the improved therapeutic activity of ATRA (natural retinoid) for acute promyelocytic leukemia by comparing with the corresponding PET probe [(11)C]Tamibarotene (artificial retinoid). PMID:24930828

  4. 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. PMID:19535255

  5. (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. PMID:24786133

  6. Brain regional pharmacokinetics of /sup 11/C-labeled diphenylhydantoin: positron emission tomography in humans

    SciTech Connect

    Baron, J.C.; Roeda, D.; Munari, C.; Crouzel, C.; Chodkiewicz, J.P.; Comar, D.

    1983-05-01

    We used positron emission tomography to study the regional cerebral pharmacokinetics of /sup 11/C-labeled diphenylhydantoin (/sup 11/C-DPH), which was given intravenously to 10 patients (8 intractable partial epileptics and 2 nonepileptics). In the nonaffected hemisphere, /sup 11/C-DPH concentration in gray matter reached equilibrium with blood within 20 minutes but was still rising at 60 minutes in white matter, where equilibrium was too slow to be detected owing to the fast physical decay of /sup 11/C. Brain-blood concentration ratios at 50 minutes were 1.37 and 1.06 in gray and white matter, respectively, similar but less variable than steady-state DPH ratios reported in human brain surgical samples. There was no indication that normal brain regions of medically resistant epileptics bind DPH less effectively than in nonepileptic patients. Brain and blood /sup 11/C-DPH concentrations were well correlated, confirming that the latter gives a reliable estimate of the former in unaffected brain regions.

  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. (11) C-labeled and (18) F-labeled PET ligands for subtype-specific imaging of histamine receptors in the brain.

    PubMed

    Funke, Uta; Vugts, Danielle J; Janssen, Bieneke; Spaans, Arnold; Kruijer, Perry S; Lammertsma, Adriaan A; Perk, Lars R; Windhorst, Albert D

    2013-01-01

    The signaling molecule histamine plays a key role in the mediation of immune reactions, in gastric secretion, and in the sensory system. In addition, it has an important function as a neurotransmitter in the central nervous system, acting in pituitary hormone secretion, wakefulness, motor and cognitive functions, as well as in itch and nociception. This has raised interest in the role of the histaminergic system for the treatment and diagnosis of various pathologies such as allergy, sleeping and eating disorders, neurodegeneration, neuroinflammation, mood disorders, and pruritus. In the past 20 years, several ligands targeting the four different histamine receptor subtypes have been explored as potential radiotracers for positron emission tomography (PET). This contribution provides an overview of the developments of subtype-selective carbon-11-labeled and fluorine-18-labeled compounds for imaging in the brain. Using specific radioligands, the H1 R expression in human brain could be examined in diseases such as schizophrenia, depression, and anorexia nervosa. In addition, the sedative effects of antihistamines could be investigated in terms of H1 R occupancy. The H3 R is of special interest because of its regulatory role in the release of various other neurotransmitters, and initial H3 R PET imaging studies in humans have been reported. The H4 R is the youngest member of the histamine receptor family and is involved in neuroinflammation and various sensory pathways. To date, two H4 R-specific (11) C-labeled ligands have been synthesized, and the imaging of the H4 R in vivo is in the early stage. PMID:24285318

  9. Rapid analysis for metabolites of 11C-labelled drugs: fate of [11C]-S-4-(tert.-butylamino-2-hydroxypropoxy)-benzimidazol-2-one in the dog.

    PubMed

    Jones, H A; Rhodes, C G; Law, M P; Becket, J M; Clark, J C; Boobis, A R; Taylor, G W

    1991-10-01

    Positron emission tomography (PET) requires the use of compounds labelled with short-lived, positron-emitting isotopes (e.g., t1/2 of 11C approximately 120 min). As the concentration of unbound, non-metabolised drug is required as the input function for modeling, this presents particular problems for the study of the kinetics and metabolism of such compounds. We have now developed a rapid extraction procedure, followed by high-performance liquid chromatography using a short analytical column coupled to an on-line gamma-detector to determine the metabolism and kinetics of a non-selective beta-adrenergic antagonist of high affinity, S-4-(tert.-butylamino-2-hydroxypropoxy)benzimidazol-2-one. This antagonist is potentially well suited to the non-invasive localisation of beta-receptors in vivo. The ligand was rapidly taken up into the beta-receptor pool or excreted in urine, with less than 5% of the drug converted to metabolites. Plasma protein binding was only 16%. No significant metabolism of the ligand was observed in the anaesthetised dog, and, therefore, no correction for blood metabolite concentration is required for kinetic analysis of the 11C-labelled ligand during PET studies in this species. The analytical method reported here should be widely applicable: quantification of metabolites enables accurate estimation of the input function and is critical to the interpretation of PET data. PMID:1686775

  10. 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. PMID:27308894

  11. Synthesis of (11)C-Labeled Thiamine and Fursultiamine for in Vivo Molecular Imaging of Vitamin B1 and Its Prodrug Using Positron Emission Tomography.

    PubMed

    Doi, Hisashi; Mawatari, Aya; Kanazawa, Masakatsu; Nozaki, Satoshi; Nomura, Yukihiro; Kitayoshi, Takahito; Akimoto, Kouji; Suzuki, Masaaki; Ninomiya, Shinji; Watanabe, Yasuyoshi

    2015-06-19

    To enable in vivo analysis of the kinetics of vitamin B1 (thiamine) and its derivatives by positron emission tomography (PET), (11)C-labeled thiamine ([(11)C]-1) has been synthesized. This was carried out via a rapid, multistep synthesis consisting of Pd(0)-mediated C-[(11)C]methylation of a thiazole ring for 3 min and benzylation with 5-(bromomethyl)pyrimidine for 7 min. The [(11)C]-1 was also converted to (11)C-labeled fursultiamine ([(11)C]-2), a prodrug of vitamin B1, by disulfide formation with S-tetrahydrofurfurylthiosulfuric acid sodium salt. Characterization of [(11)C]-1 and [(11)C]-2 showed them to be suitable for use as PET probes for in vivo pharmacokinetic and medical studies. The total durations of the preparations of [(11)C]-1 and [(11)C]-2 were shorter than 60 and 70 min, respectively. The [(11)C]CH3I-based decay-corrected radiochemical yields of [(11)C]-1 and [(11)C]-2 were 9-16% and 4-10%, respectively. The radioactivities of the final injectable solutions of [(11)C]-1 and [(11)C]-2 were 400-700 and 100-250 MBq, respectively. The radiochemical purity of both [(11)C]-1 and [(11)C]-2 was 99%, and the chemical purities of [(11)C]-1 and [(11)C]-2 were 99% and 97-99%, respectively. In vivo PET imaging of normal rats was illustrated by the distribution of [(11)C]-1 and [(11)C]-2 following intravenous injection. PMID:25984933

  12. Evaluation of myocardial metabolism, with /sup 13/N- and /sup 11/C-labeled amino acids and positron computed tomography

    SciTech Connect

    Henze, E.; Schelbert, H.R.; Barrio, J.R.; Egbert, J.E.; Hansen, H.W.; MacDonald, N.S.; Phelps, M.E.

    1982-08-01

    To evaluate the utility of labeled L-amino acids (AA) for imaging regional myocardial AA metabolism by positron computed tomography (PCT), the myocardial uptake and clearance of Ala,* Glu, Gln, Asp, Leu tagged with /sup 13/N, and of /sup 11/C-tagged Asp, and oxaloacetate (Oxal), were examined in 44 experiments at control, during ischemia, and after transaminase inhibition. The myocardial time-activity curves recorded after intracoronary tracer injection had two clearance phases (an early and a late) for all /sup 13/N AA, and three (early, intermediate, late) for the two /sup 11/C compounds, with significantly different clearance half-times of 18.7 +/- 8.0 (s.d.) sec for the early phase, 141.7 +/- 56.5 sec for the intermediate, and 61.2 +/- 43.5 min for the late phase. The residual fractions ranged from 0.07 to 0.23 in normal myocardium, and consistently increased with ischemia by 0.01-0.07 for /sup 13/N-labeled Ala, Glu, Asp, and Leu, but not for /sup 13/N Gln and /sup 11/C compounds. Transaminase inhibition shortened the half-times of the late phases of /sup 13/N-labeled Ala, Glu, Asp, and Leu; had no effect on t1/2 of /sup 13/N Gln and /sup 11/C Oxal; and resulted in a loss of /sup 11/C CO/sub 2/ production and of the intermediate phase for /sup 11/C Asp. On the PCT images, /sup 13/N activity from labeled Ala and Glu was not decreased in an ischemic segment despite a significant flow reduction, as demonstrated by /sup 13/N NH/sub 3/ imaging and labeled microspheres. From the results, a three-compartment tracer kinetic model is proposed for the noninvasive quantification of Krebscycle activity, protein synthesis, and metabolic derangements related to ischemia.

  13. Cheminformatics approaches to analyze diversity in compound screening libraries.

    PubMed

    Akella, Lakshmi B; DeCaprio, David

    2010-06-01

    As high-throughput screening matures as a discipline, cheminformatics is playing an increasingly important role in selecting new compounds for diverse screening libraries. New visualization techniques such as multi-fusion similarity maps, scaffold trees, and principal moments of inertia plots provide complementary information on compound libraries and enable identification of unexplored regions of chemical space with potential biological relevance. Quantitative metrics have been developed to analyze libraries for properties such as natural product-likeness and shape complexity. Analysis of high-throughput screening results and drug discovery programs identify compounds problematic for screening. Taken together these approaches allow us to increase the diversity of biological outcomes available in compound screening libraries and improve the success rates of high-throughput screening against new targets without making significant increases in the size of compound libraries. PMID:20457001

  14. Increase of 20-HETE synthase after brain ischemia in rats revealed by PET study with 11C-labeled 20-HETE synthase-specific inhibitor

    PubMed Central

    Kawasaki, Toshiyuki; Marumo, Toshiyuki; Shirakami, Keiko; Mori, Tomoko; Doi, Hisashi; Suzuki, Masaaki; Watanabe, Yasuyoshi; Chaki, Shigeyuki; Nakazato, Atsuro; Ago, Yukio; Hashimoto, Hitoshi; Matsuda, Toshio; Baba, Akemichi; Onoe, Hirotaka

    2012-01-01

    20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid metabolite known to be produced after cerebral ischemia, has been implicated in ischemic and reperfusion injury by mediating vasoconstriction. To develop a positron emission tomography (PET) probe for 20-HETE synthase imaging, which might be useful for monitoring vasoconstrictive processes in patients with brain ischemia, we synthesized a 11C-labeled specific 20-HETE synthase inhibitor, N′(4-dimethylaminohexyloxy)phenyl imidazole ([11C]TROA). Autoradiographic study showed that [11C]TROA has high-specific binding in the kidney and liver consistent with the previously reported distribution of 20-HETE synthase. Using transient middle cerebral artery occlusion in rats, PET study showed significant increases in the binding of [11C]TROA in the ipsilateral hemisphere of rat brains after 7 and 10 days, which was blocked by co-injection of excess amounts of TROA (10 mg/kg). The increased [11C]TROA binding on the ipsilateral side returned to basal levels within 14 days. In addition, quantitative real-time PCR revealed that increased expression of 20-HETE synthase was only shown on the ipsilateral side on day 7. These results indicate that [11C]TROA might be a useful PET probe for imaging of 20-HETE synthase in patients with cerebral ischemia. PMID:22669478

  15. [11C]-Labeled Metformin Distribution in the Liver and Small Intestine Using Dynamic Positron Emission Tomography in Mice Demonstrates Tissue-Specific Transporter Dependency.

    PubMed

    Jensen, Jonas B; Sundelin, Elias I; Jakobsen, Steen; Gormsen, Lars C; Munk, Ole L; Frøkiær, Jørgen; Jessen, Niels

    2016-06-01

    Metformin is the most commonly prescribed oral antidiabetic drug, with well-documented beneficial preventive effects on diabetic complications. Despite being in clinical use for almost 60 years, the underlying mechanisms for metformin action remain elusive. Organic cation transporters (OCT), including multidrug and toxin extrusion proteins (MATE), are essential for transport of metformin across membranes, but tissue-specific activity of these transporters in vivo is incompletely understood. Here, we use dynamic positron emission tomography with [(11)C]-labeled metformin ([(11)C]-metformin) in mice to investigate the role of OCT and MATE in a well-established target tissue, the liver, and a putative target of metformin, the small intestine. Ablation of OCT1 and OCT2 significantly reduced the distribution of metformin in the liver and small intestine. In contrast, inhibition of MATE1 with pyrimethamine caused accumulation of metformin in the liver but did not affect distribution in the small intestine. The demonstration of OCT-mediated transport into the small intestine provides evidence of direct effects of metformin in this tissue. OCT and MATE have important but separate roles in uptake and elimination of metformin in the liver, but this is not due to changes in biliary secretion. [(11)C]-Metformin holds great potential as a tool to determine the pharmacokinetic properties of metformin in clinical studies. PMID:26993065

  16. 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). PMID:27316988

  17. The Design and Application of Target-Focused Compound Libraries

    PubMed Central

    Harris, C. John; Hill, Richard D; Sheppard, David W; Slater, Martin J; Stouten, Pieter F.W

    2011-01-01

    Target-focused compound libraries are collections of compounds which are designed to interact with an individual protein target or, frequently, a family of related targets (such as kinases, voltage-gated ion channels, serine/cysteine proteases). They are used for screening against therapeutic targets in order to find hit compounds that might be further developed into drugs. The design of such libraries generally utilizes structural information about the target or family of interest. In the absence of such structural information, a chemogenomic model that incorporates sequence and mutagenesis data to predict the properties of the binding site can be employed. A third option, usually pursued when no structural data are available, utilizes knowledge of the ligands of the target from which focused libraries can be developed via scaffold hopping. Consequently, the methods used for the design of target-focused libraries vary according to the quantity and quality of structural or ligand data that is available for each target family. This article describes examples of each of these design approaches and illustrates them with case studies, which highlight some of the issues and successes observed when screening target-focused libraries. PMID:21521154

  18. 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/). PMID:25205347

  19. GPU Accelerated Chemical Similarity Calculation for Compound Library Comparison

    PubMed Central

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

    2012-01-01

    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 multi-core 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 minutes to complete the calculation of Tanimoto coefficients between 32M PubChem compounds and 10K Active Probes compounds, i.e., 324G Tanimoto coefficients, on a 128-CUDA-core GPU. PMID:21692447

  20. Web enabling technology for the design, enumeration, optimization and tracking of compound libraries.

    PubMed

    Feuston, Bradley P; Chakravorty, Subhas J; Conway, John F; Culberson, J Christopher; Forbes, Joseph; Kraker, Bryan; Lennon, Patricia A; Lindsley, Craig; McGaughey, Georgia B; Mosley, Ralph; Sheridan, Robert P; Valenciano, Mario; Kearsley, Simon K

    2005-01-01

    Motivated by the need to augment Merck's in-house small molecule collection, web-based tools for designing, enumerating, optimizing and tracking compound libraries have been developed. The path leading to the current version of this Virtual Library Tool Kit (VLTK) is discussed in context of the (then) available commercial offerings and the constraints and requirements imposed by the end users. Though the effort was initiated to simplify the tasks of designing novel, drug-like and diverse compound libraries containing between 2K-10K unique entities, it has also evolved into a powerful tool for outsourcing syntheses as well as lead identification and optimization. The web tool includes components that select reagents, analyze synthons, identify backup reagents, enumerate libraries, calculate properties, optimize libraries and finally track the synthesized compounds through biological assays. In addition to accommodating project specific designs and virtual 3D library scanning, the application includes tools for parallel synthesis, laboratory automation and compound registration. PMID:16101417

  1. One-bead-one-compound library of end-capped dipeptides and deconvolution by microflow NMR.

    PubMed

    Simon, Rozalyn A; Schuresko, Laura; Dendukuri, Nagamani; Goers, Emily; Murphy, Brent; Lokey, R Scott

    2005-01-01

    As part of our program to identify novel small molecules with interesting biological activity, we have designed and synthesized a library of end-capped dipeptides with an emphasis on compound diversity, complexity, and membrane permeability. An approximately 1500-member library was synthesized manually on large polystyrene beads using the mix-and-split method. The final compounds were cleaved into 384-well plates to generate individual stock solutions for input into high-throughput biological screens. Individual compounds were decoded using a combination of mass spectrometry and microflow NMR spectroscopy. In principle, this approach to deconvolution obviates the need for complicated binary encoding-decoding strategies for one-bead-one-compound libraries. PMID:16153064

  2. Design, synthesis, and biological evaluation of a biyouyanagin compound library.

    PubMed

    Nicolaou, K C; Sanchini, Silvano; Sarlah, David; Lu, Gang; Wu, T Robert; Nomura, Daniel K; Cravatt, Benjamin F; Cubitt, Beatrice; de la Torre, Juan C; Hessell, Ann J; Burton, Dennis R

    2011-04-26

    Modern drug discovery efforts rely, to a large extent, on lead compounds from two classes of small organic molecules; namely, natural products (i.e., secondary metabolites) and designed compounds (i.e., synthetic molecules). In this article, we demonstrate how these two domains of lead compounds can be merged through total synthesis and molecular design of analogs patterned after the targeted natural products, whose promising biological properties provide the motivation. Specifically, the present study targeted the naturally occurring biyouyanagins A and B and their analogs through modular chemical synthesis and led to the discovery of small organic molecules possessing anti-HIV and anti-arenavirus properties. PMID:21245351

  3. Investigation of the incidence of "undesirable" molecular moieties for high-throughput screening compound libraries in marketed drug compounds.

    PubMed

    Axerio-Cilies, Peter; Castañeda, Ivan P; Mirza, Amin; Reynisson, Jóhannes

    2009-03-01

    A database of 1070 marketed drug compounds was compiled and analyzed in order to assess the occurrence of moieties described in the literature as "undesirable" for high-throughput screening compound libraries due to their ability to perturb assay formats. The study revealed a total of 277 compounds, 26% of the database, contained at least one of the moieties. As some of the drug compounds contained more than one "undesirable" moiety, the total number was 352. Electrophilic reactive groups, particularly aliphatic esters, were the most abundant type with 55% of the total. Half of the drug compounds incorporating the "undesirable" moieties were synthetic organic molecules. These findings suggest that "undesirable" moieties do not pose a major hindrance during clinical trials, the most expensive phase of drug development. In addition, their early elimination in the preclinical stage excludes large regions of known drug space due to the reliance on biochemical and cell-based assays. In general, it can be concluded that compounds with "undesirable" moieties should not simply be eliminated from compound screening libraries but rather be flagged as potentially problematic. A possible solution is to segregate the compounds containing suspect moieties and screen them when deemed appropriate. PMID:18692938

  4. Direct Comparison of Linear and Macrocyclic Compound Libraries as a Source of Protein Ligands

    PubMed Central

    2015-01-01

    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. PMID:25623285

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

    PubMed Central

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

    2008-01-01

    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. PMID:18663392

  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. PMID:22326864

  7. Design of a general-purpose European compound screening library for EU-OPENSCREEN.

    PubMed

    Horvath, Dragos; Lisurek, Michael; Rupp, Bernd; Kühne, Ronald; Specker, Edgar; von Kries, Jens; Rognan, Didier; Andersson, C David; Almqvist, Fredrik; Elofsson, Mikael; Enqvist, Per-Anders; Gustavsson, Anna-Lena; Remez, Nikita; Mestres, Jordi; Marcou, Gilles; Varnek, Alexander; Hibert, Marcel; Quintana, Jordi; Frank, Ronald

    2014-10-01

    This work describes a collaborative effort to define and apply a protocol for the rational selection of a general-purpose screening library, to be used by the screening platforms affiliated with the EU-OPENSCREEN initiative. It is designed as a standard source of compounds for primary screening against novel biological targets, at the request of research partners. Given the general nature of the potential applications of this compound collection, the focus of the selection strategy lies on ensuring chemical stability, absence of reactive compounds, screening-compliant physicochemical properties, loose compliance to drug-likeness criteria (as drug design is a major, but not exclusive application), and maximal diversity/coverage of chemical space, aimed at providing hits for a wide spectrum of drugable targets. Finally, practical availability/cost issues cannot be avoided. The main goal of this publication is to inform potential future users of this library about its conception, sources, and characteristics. The outline of the selection procedure, notably of the filtering rules designed by a large committee of European medicinal chemists and chemoinformaticians, may be of general methodological interest for the screening/medicinal chemistry community. The selection task of 200K molecules out of a pre-filtered set of 1.4M candidates was shared by five independent European research groups, each picking a subset of 40K compounds according to their own in-house methodology and expertise. An in-depth analysis of chemical space coverage of the library serves not only to characterize the collection, but also to compare the various chemoinformatics-driven selection procedures of maximal diversity sets. Compound selections contributed by various participating groups were mapped onto general-purpose self-organizing maps (SOMs) built on the basis of marketed drugs and bioactive reference molecules. In this way, the occupancy of chemical space by the EU-OPENSCREEN library could

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

    PubMed Central

    2012-01-01

    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. PMID:23006594

  9. 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…

  10. 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. PMID:19569201

  11. 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. PMID:25883137

  12. 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

  13. Design and Synthesis of Fsp(3)-Rich, Bis-Spirocyclic-Based Compound Libraries for Biological Screening.

    PubMed

    Stotani, Silvia; Lorenz, Christoph; Winkler, Matthias; Medda, Federico; Picazo, Edwige; Ortega Martinez, Raquel; Karawajczyk, Anna; Sanchez-Quesada, Jorge; Giordanetto, Fabrizio

    2016-06-13

    The exploration of innovative chemical space is a critical step in the early phases of drug discovery. Bis-spirocyclic frameworks occur in natural products and other biologically relevant metabolites and show attractive features, such as molecular compactness, structural complexity, and three-dimensional character. A concise approach to the synthesis of bis-spirocyclic-based compound libraries starting from readily available commercial reagents and robust chemical transformations has been developed. A number of novel bis-spirocyclic scaffold examples, as implemented in the European Lead Factory project, is presented. PMID:27163646

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

    PubMed Central

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

    2011-01-01

    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. PMID:21353727

  15. Identification of entry inhibitors of Ebola virus pseudotyped vectors from a myxobacterial compound library.

    PubMed

    Beck, Simon; Henß, Lisa; Weidner, Tatjana; Herrmann, Jennifer; Müller, Rolf; Chao, Yu-Kai; Grimm, Christian; Weber, Christopher; Sliva, Katja; Schnierle, Barbara S

    2016-08-01

    Myxobacteria produce secondary metabolites many of which were described to have various biological effects including anti-fungal, anti-bacterial and anti-viral activity. The majority of these metabolites are novel scaffolds with unique modes-of-action and hence might be potential leads for drug discovery. Here, we tested a myxobacterial natural product library for compounds with inhibitory activity against Ebola virus (EBOV). The assay was performed with a surrogate system using Ebola envelope glycoprotein (GP) pseudotyped lentiviral vectors. EBOV specificity was proven by counter-screening with vesicular stomatitis virus G protein pseudotyped vectors. Two compounds were identified that preferentially inhibited EBOV GP mediated cell entry: Chondramides that act on the actin skeleton but might be too toxic and noricumazole A, a potassium channel inhibitor, which might constitute a novel pathway to inhibit Ebola virus cell entry. PMID:27241689

  16. 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

  17. Screening of antitubercular compound library identifies novel shikimate kinase inhibitors of Mycobacterium tuberculosis.

    PubMed

    Rajput, Vikrant S; Mehra, Rukmankesh; Kumar, Sanjay; Nargotra, Amit; Singh, Parvinder Pal; Khan, Inshad Ali

    2016-06-01

    Shikimate kinase of Mycobacterium tuberculosis is involved in the biosynthesis of aromatic amino acids through shikimate pathway. The enzyme is essential for the survival of M. tuberculosis and is absent from mammals, thus providing an excellent opportunity for identifying new chemical entities to combat tuberculosis with a novel mechanism of action. In this study, an antitubercular library of 1000 compounds was screened against M. tuberculosis shikimate kinase (MtSK). This effort led to the identification of 20 inhibitors, among which five promising leads exhibited half maximal inhibitory concentration (IC50) values below 10 μM. The most potent inhibitor ("5631296") showed an IC50 value of 5.10 μM ± 0.6. The leads were further evaluated for the activity against multidrug-resistant (MDR)-TB, Gram-positive and Gram-negative bacterial strains, mode of action, docking simulations, and combinatorial study with three frontline anti-TB drugs. Compound "5491210" displayed a nearly synergistic activity with rifampicin, isoniazid, and ethambutol while compound "5631296" was synergistic with rifampicin. In vitro cytotoxicity against HepG2 cell line was evaluated and barring one compound; all were found to be non-toxic (SI > 10). In order to rule out mitochondrial toxicity, the promising inhibitors were also evaluated for cell cytotoxicity using galactose medium where compounds "5631296" and "5122752" appeared non-toxic. Upon comprehensive analysis, compound "5631296" was found to be the most promising MtSK inhibitor that was safe, synergistic with rifampicin, and bactericidal against M. tuberculosis. PMID:26887318

  18. 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

  19. 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.

  20. 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

    2016-01-01

    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

  1. 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. PMID:26025037

  2. An Automated Microwave-Assisted Synthesis Purification System for Rapid Generation of Compound Libraries.

    PubMed

    Tu, Noah P; Searle, Philip A; Sarris, Kathy

    2016-06-01

    A novel methodology for the synthesis and purification of drug-like compound libraries has been developed through the use of a microwave reactor with an integrated high-performance liquid chromatography-mass spectrometry (HPLC-MS) system. The strategy uses a fully automated synthesizer with a microwave as energy source and robotic components for weighing and dispensing of solid reagents, handling liquid reagents, capper/crimper of microwave reaction tube assemblies, and transportation. Crude reaction products were filtered through solid-phase extraction cartridges and injected directly onto a reverse-phase chromatography column via an injection valve. For multistep synthesis, crude products were passed through scavenger resins and reintroduced for subsequent reactions. All synthetic and purification steps were conducted under full automation with no handling or isolation of intermediates, to afford the desired purified products. This approach opens the way to highly efficient generation of drug-like compounds as part of a lead discovery strategy or within a lead optimization program. PMID:26085482

  3. 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. PMID:27124678

  4. Structures of endothiapepsin-fragment complexes from crystallographic fragment screening using a novel, diverse and affordable 96-compound fragment library.

    PubMed

    Huschmann, Franziska U; Linnik, Janina; Sparta, Karine; Ühlein, Monika; Wang, Xiaojie; Metz, Alexander; Schiebel, Johannes; Heine, Andreas; Klebe, Gerhard; Weiss, Manfred S; Mueller, Uwe

    2016-05-01

    Crystallographic screening of the binding of small organic compounds (termed fragments) to proteins is increasingly important for medicinal chemistry-oriented drug discovery. To enable such experiments in a widespread manner, an affordable 96-compound library has been assembled for fragment screening in both academia and industry. The library is selected from already existing protein-ligand structures and is characterized by a broad ligand diversity, including buffer ingredients, carbohydrates, nucleotides, amino acids, peptide-like fragments and various drug-like organic compounds. When applied to the model protease endothiapepsin in a crystallographic screening experiment, a hit rate of nearly 10% was obtained. In comparison to other fragment libraries and considering that no pre-screening was performed, this hit rate is remarkably high. This demonstrates the general suitability of the selected compounds for an initial fragment-screening campaign. The library composition, experimental considerations and time requirements for a complete crystallographic fragment-screening campaign are discussed as well as the nine fully refined obtained endothiapepsin-fragment structures. While most of the fragments bind close to the catalytic centre of endothiapepsin in poses that have been observed previously, two fragments address new sites on the protein surface. ITC measurements show that the fragments bind to endothiapepsin with millimolar affinity. PMID:27139825

  5. 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. PMID:26414664

  6. 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

  7. 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. PMID:20981530

  8. Screen of FDA-approved drug library reveals compounds that protect hair cells from aminoglycosides and cisplatin

    PubMed Central

    Vlasits, Anna L.; Simon, Julian A.; Raible, David W.; Rubel, Edwin W; Owens, Kelly N.

    2012-01-01

    Loss of mechanosensory hair cells in the inner ear accounts for many hearing loss and balance disorders. Several beneficial pharmaceutical drugs cause hair cell death as a side effect. These include aminoglycoside antibiotics, such as neomycin, kanamycin and gentamicin, and several cancer chemotherapy drugs, such as cisplatin. Discovering new compounds that protect mammalian hair cells from toxic insults is experimentally difficult because of the inaccessibility of the inner ear. We used the zebrafish lateral line sensory system as an in vivo screening platform to survey a library of FDA-approved pharmaceuticals for compounds that protect hair cells from neomycin, gentamicin, kanamycin and cisplatin. Ten compounds were identified that provide protection from at least two of the four toxins. The resulting compounds fall into several drug classes, including serotonin and dopamine-modulating drugs, adrenergic receptor ligands, and estrogen receptor modulators. The protective compounds show different effects against the different toxins, supporting the idea that each toxin causes hair cell death by distinct, but partially overlapping, mechanisms. Furthermore, some compounds from the same drug classes had different protective properties, suggesting that they might not prevent hair cell death by their known target mechanisms. Some protective compounds blocked gentamicin uptake into hair cells, suggesting that they may block mechanotransduction or other routes of entry. The protective compounds identified in our screen will provide a starting point for studies in mammals as well as further research discovering the cellular signaling pathways that trigger hair cell death. PMID:22967486

  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. 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

  12. 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

  13. Sensitive electrospray mass spectrometry analysis of one-bead-one-compound peptide libraries labeled by quaternary ammonium salts.

    PubMed

    Bąchor, Remigiusz; Cydzik, Marzena; Rudowska, Magdalena; Kluczyk, Alicja; Stefanowicz, Piotr; Szewczuk, Zbigniew

    2012-08-01

    A rapid and straightforward method for high-throughput analysis of single resin beads from one-bead-one-compound combinatorial libraries with high resolution electrospray ionization tandem mass spectrometry (HR ESI-MS/MS) is presented. The application of an efficient method of peptide derivatization by quaternary ammonium salts (QAS) formation increases ionization efficiency and reduces the detection limit, allowing analysis of trace amounts of compounds by ESI-MS. Peptides, synthesized on solid support, contain a new cleavable linker composed of a Peg spacer (9-aza-3,6,12,15-tetraoxa-10-on-heptadecanoic acid), lysine with ɛ-amino group marked by the N,N,N-triethylglycine salt, and methionine, which makes possible the selective cleavage by cyanogen bromide. Even a small portion of peptides derivatized by QAS cleaved from a single resin bead is sufficient for sequencing by HR ESI-MS/MS experiments. The developed strategy was applied to a small training library of α chymotrypsin substrates. The obtained results confirm the applicability of the proposed method in combinatorial chemistry. PMID:22740104

  14. COMPARISON OF SIMCA PATTERN RECOGNITION & LIBRARY SEARCH IDENTIFICATION OF HAZARDOUS COMPOUNDS FROM MASS SPECTRA

    EPA Science Inventory

    SIMCA pattern recognition methods have been applied to mass spectral data from a target list of hazardous chemicals. cheme has been proposed for classification and identification of five classes of compounds including aromatics, chlorocarbons, bromocarbons, hydrocarbons, and poly...

  15. COMPARISON OF SIMCA PATTERN RECOGNITION AND LIBRARY SEARCH IDENTIFICATION OF HAZARDOUS COMPOUNDS FROM MASS SPECTRA

    EPA Science Inventory

    SIMCA pattern recognition methods have been applied to mass spectral data from a target list of hazardous chemicals. cheme has been proposed for classification and identification of five classes of compounds including aromatics, chlorocarbons, bromocarbons, hydrocarbons, and poly...

  16. 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

  17. 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

  18. 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

  19. 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. PMID:22064367

  20. 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. PMID:27227368

  1. Classification scheme for the design of serine protease targeted compound libraries.

    PubMed

    Lang, Stanley A; Kozyukov, Andrey V; Balakin, Konstantin V; Skorenko, Andrey V; Ivashchenko, Andrey A; Savchuk, Nikolay P

    2002-11-01

    The development of a scoring scheme for the classification of molecules into serine protease (SP) actives and inactives is described. The method employed a set of pre-selected descriptors for encoding the molecular structures, and a trained neural network for classifying the molecules. The molecular requirements were profiled and validated by using available databases of SP- and non-SP-active agents [1,439 diverse SP-active molecules, and 5,131 diverse non-SP-active molecules from the Ensemble Database (Prous Science, 2002)] and Sensitivity Analysis. The method enables an efficient qualification or disqualification of a molecule as a potential serine protease ligand. It represents a useful tool for constraining the size of virtual libraries that will help accelerate the development of new serine protease active drugs. PMID:12825792

  2. Preparation of a 990-member chemical compound library of hydantoin- and isoxazoline-containing heterocycles using multipin technology.

    PubMed

    Park, K H; Ehrler, J; Spoerri, H; Kurth, M J

    2001-01-01

    The development of a useful chemistry for the construction of polyfunctional heterocycles--first through solution and solid phase (resins) and then library production via SynPhase crowns--is reported. Bead-based synthetic work was done on Merrifield resin where treatment with benzylamine in the presence of DBU followed by reaction with 4-chloromethylbenzoyl chloride afforded amide-linked resin 9. Finally, TFA.NH2-polystyrene macro crowns were derivatized with 4-(hydroxymethyl)benzoic acid to afford pin 14 which was coupled with Boc-protected amino acid 2 in the presence of DIC to deliver pin 15. Deprotection and reaction with phenyl isocyanate afforded urea functionalized pin 17 which underwent 1,3-dipolar cycloaddition reaction to give pin 19. Finally, compound 20 was obtained with moderate diastereoselectivity (20:21::8:1) by the reaction of pin 19 with a catalytic amount of Et3N. PMID:11300857

  3. Identification of Novel Compounds Inhibiting Chikungunya Virus-Induced Cell Death by High Throughput Screening of a Kinase Inhibitor Library

    PubMed Central

    Gomes, Rafael G. B.; da Silva, Camila T.; Taniguchi, Juliana B.; No, Joo Hwan; Lombardot, Benoit; Schwartz, Olivier; Hansen, Michael A. E.; Freitas-Junior, Lucio H.

    2013-01-01

    Chikungunya virus (CHIKV) is a mosquito-borne arthrogenic alphavirus that causes acute febrile illness in humans accompanied by joint pains and in many cases, persistent arthralgia lasting weeks to years. The re-emergence of CHIKV has resulted in numerous outbreaks in the eastern hemisphere, and threatens to expand in the foreseeable future. Unfortunately, no effective treatment is currently available. The present study reports the use of resazurin in a cell-based high-throughput assay, and an image-based high-content assay to identify and characterize inhibitors of CHIKV-infection in vitro. CHIKV is a highly cytopathic virus that rapidly kills infected cells. Thus, cell viability of HuH-7 cells infected with CHIKV in the presence of compounds was determined by measuring metabolic reduction of resazurin to identify inhibitors of CHIKV-associated cell death. A kinase inhibitor library of 4,000 compounds was screened against CHIKV infection of HuH-7 cells using the resazurin reduction assay, and the cell toxicity was also measured in non-infected cells. Seventy-two compounds showing ≥50% inhibition property against CHIKV at 10 µM were selected as primary hits. Four compounds having a benzofuran core scaffold (CND0335, CND0364, CND0366 and CND0415), one pyrrolopyridine (CND0545) and one thiazol-carboxamide (CND3514) inhibited CHIKV-associated cell death in a dose-dependent manner, with EC50 values between 2.2 µM and 7.1 µM. Based on image analysis, these 6 hit compounds did not inhibit CHIKV replication in the host cell. However, CHIKV-infected cells manifested less prominent apoptotic blebs typical of CHIKV cytopathic effect compared with the control infection. Moreover, treatment with these compounds reduced viral titers in the medium of CHIKV-infected cells by up to 100-fold. In conclusion, this cell-based high-throughput screening assay using resazurin, combined with the image-based high content assay approach identified compounds against CHIKV having a novel

  4. 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. PMID:25801335

  5. 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. PMID:24409958

  6. Rainbow beads: a color coding method to facilitate high-throughput screening and optimization of one-bead one-compound combinatorial libraries.

    PubMed

    Luo, Juntao; Zhang, Hongyong; Xiao, Wenwu; Kumaresan, Pappanaicken R; Shi, Changying; Pan, Chong-Xian; Aina, Olulanu H; Lam, Kit S

    2008-01-01

    We have developed a new color-encoding method that facilitates high-throughput screening of one-bead one-compound (OBOC) combinatorial libraries. Polymer beads displaying chemical compounds or families of compounds are stained with oil-based organic dyes that are used as coding tags. The color dyes do not affect cell binding to the compounds displayed on the surface of the beads. We have applied such rainbow beads in a multiplex manner to discover and profile ligands against cell surface receptors. In the first application, a series of OBOC libraries with different scaffolds or motifs are each color-coded; small samples of each library are then combined and screened concurrently against live cells for cell attachment. Preferred libraries can be rapidly identified and selected for subsequent large-scale screenings for cell surface binding ligands. In a second application, beads with a series of peptide analogues (e.g., alanine scan) are color-coded, combined, and tested for binding against a specific cell line in a single-tissue culture well; the critical residues required for binding can be easily determined. In a third application, ligands reacting against a series of integrins are color-coded and used as a readily applied research tool to determine the integrin profile of any cell type. One major advantage of this straightforward and yet powerful method is that only an ordinary inverted microscope is needed for the analysis, instead of sophisticated (and expensive) fluorescent microscopes or flow cytometers. PMID:18558750

  7. 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.

  8. 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.

  9. 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

  10. Screening One-Bead-One-Compound Peptide Libraries for Optimal Kinase Substrates.

    PubMed

    Trinh, Thi B; Pei, Dehua

    2016-01-01

    Protein kinases phosphorylate specific serine, threonine, and/or tyrosine residues in their target proteins, resulting in functional changes of the target proteins such as enzymatic activity, cellular location, or association with other proteins. For many kinases, their in vivo substrate specificity is at least partially defined by the amino acid sequence surrounding the phosphorylatable residue (or sequence specificity). We report here a robust, high-throughput method for profiling the sequence specificity of protein kinases. Up to 10(7) different peptides are rapidly synthesized on PEGA beads in the one-bead-one-compound format and subjected to kinase reaction in the presence of [γ-S]ATP. Positive beads displaying the optimal kinase substrates are identified by covalently labeling the thiophosphorylated peptides with a fluorescent dye via a disulfide exchange reaction. Finally, the most active hit(s) is identified by the partial Edman degradation-mass spectrometry (PED-MS) method. The ability of this method to provide individual sequences of the preferred substrates permits the identification of sequence contextual effects and non-permissive residues. This method is applicable to protein serine, threonine, and tyrosine kinases. PMID:26501910

  11. Acoustic Sample Deposition MALDI-MS (ASD-MALDI-MS): A Novel Process Flow for Quality Control Screening of Compound Libraries.

    PubMed

    Chin, Jefferson; Wood, Elizabeth; Peters, Grace S; Drexler, Dieter M

    2016-02-01

    In the early stages of drug discovery, high-throughput screening (HTS) of compound libraries against pharmaceutical targets is a common method to identify potential lead molecules. For these HTS campaigns to be efficient and successful, continuous quality control of the compound collection is necessary and crucial. However, the large number of compound samples and the limited sample amount pose unique challenges. Presented here is a proof-of-concept study for a novel process flow for the quality control screening of small-molecule compound libraries that consumes only minimal amounts of samples and affords compound-specific molecular data. This process employs an acoustic sample deposition (ASD) technique for the offline sample preparation by depositing nanoliter volumes in an array format onto microscope glass slides followed by matrix-assisted laser desorption/ionization mass spectrometric (MALDI-MS) analysis. An initial study of a 384-compound array employing the ASD-MALDI-MS workflow resulted in a 75% first-pass positive identification rate with an analysis time of <1 s per sample. PMID:26203056

  12. 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. PMID:25695766

  13. Encoded library technology screening of hepatitis C virus NS4B yields a small-molecule compound series with in vitro replicon activity.

    PubMed

    Arico-Muendel, Christopher; Zhu, Zhengrong; Dickson, Hamilton; Parks, Derek; Keicher, Jesse; Deng, Jianghe; Aquilani, Leah; Coppo, Frank; Graybill, Todd; Lind, Kenneth; Peat, Andrew; Thomson, Michael

    2015-01-01

    To identify novel antivirals to the hepatitis C virus (HCV) NS4B protein, we utilized encoded library technology (ELT), which enables purified proteins not amenable to standard biochemical screening methods to be tested against large combinatorial libraries in a short period of time. We tested NS4B against several DNA-encoded combinatorial libraries (DEL) and identified a single DEL feature that was subsequently progressed to off-DNA synthesis. The most active of the initial synthesized compounds had 50% inhibitory concentrations (IC50s) of 50 to 130 nM in a NS4B radioligand binding assay and 300 to 500 nM in an HCV replicon assay. Chemical optimization yielded compounds with potencies as low as 20 nM in an HCV genotype 1b replicon assay, 500 nM against genotype 1a, and 5 μM against genotype 2a. Through testing against other genotypes and genotype 2a-1b chimeric replicons and from resistance passage using the genotype 1b replicon, we confirmed that these compounds were acting on the proposed first transmembrane region of NS4B. A single sequence change (F98L) was identified as responsible for resistance, and it was thought to largely explain the relative lack of potency of this series against genotype 2a. Unlike other published series that appear to interact with this region, we did not observe sensitivity to amino acid substitutions at positions 94 and 105. The discovery of this novel compound series highlights ELT as a valuable approach for identifying direct-acting antivirals to nonenzymatic targets. PMID:25824229

  14. Identification of Novel Anti-mycobacterial Compounds by Screening a Pharmaceutical Small-Molecule Library against Nonreplicating Mycobacterium tuberculosis.

    PubMed

    Warrier, Thulasi; Martinez-Hoyos, Maria; Marin-Amieva, Manuel; Colmenarejo, Gonzalo; Porras-De Francisco, Esther; Alvarez-Pedraglio, Ana Isabel; Fraile-Gabaldon, Maria Teresa; Torres-Gomez, Pedro Alfonso; Lopez-Quezada, Landys; Gold, Ben; Roberts, Julia; Ling, Yan; Somersan-Karakaya, Selin; Little, David; Cammack, Nicholas; Nathan, Carl; Mendoza-Losana, Alfonso

    2015-12-11

    Identification of compounds that target metabolically diverse subpopulations of Mycobacterium tuberculosis (Mtb) may contribute to shortening the course of treatment for tuberculosis. This study screened 270,000 compounds from GlaxoSmithKline's collection against Mtb in a nonreplicating (NR) state imposed in vitro by a combination of four host-relevant stresses. Evaluation of 166 confirmed hits led to detailed characterization of 19 compounds for potency, specificity, cytotoxicity, and stability. Compounds representing five scaffolds depended on reactive nitrogen species for selective activity against NR Mtb, and two were stable in the assay conditions. Four novel scaffolds with activity against replicating (R) Mtb were also identified. However, none of the 19 compounds was active against Mtb in both NR and R states. There was minimal overlap between compounds found active against NR Mtb and those previously identified as active against R Mtb, supporting the hypothesis that NR Mtb depends on distinct metabolic pathways for survival. PMID:27623055

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  16. A Wide-Field Fluorescence Microscope Extension for Ultrafast Screening of One-Bead One-Compound Libraries Using a Spectral Image Subtraction Approach.

    PubMed

    Heusermann, Wolf; Ludin, Beat; Pham, Nhan T; Auer, Manfred; Weidemann, Thomas; Hintersteiner, Martin

    2016-05-01

    The increasing involvement of academic institutions and biotech companies in drug discovery calls for cost-effective methods to identify new bioactive molecules. Affinity-based on-bead screening of combinatorial one-bead one-compound libraries combines a split-mix synthesis design with a simple protein binding assay operating directly at the bead matrix. However, one bottleneck for academic scale on-bead screening is the unavailability of a cheap, automated, and robust screening platform that still provides a quantitative signal related to the amount of target protein binding to individual beads for hit bead ranking. Wide-field fluorescence microscopy has long been considered unsuitable due to significant broad spectrum autofluorescence of the library beads in conjunction with low detection sensitivity. Herein, we demonstrate how such a standard microscope equipped with LED-based excitation and a modern CMOS camera can be successfully used for selecting hit beads. We show that the autofluorescence issue can be overcome by an optical image subtraction approach that yields excellent signal-to-noise ratios for the detection of bead-associated target proteins. A polymer capillary attached to a semiautomated bead-picking device allows the operator to efficiently isolate individual hit beads in less than 20 s. The system can be used for ultrafast screening of >200,000 bead-bound compounds in 1.5 h, thereby making high-throughput screening accessible to a wider group within the scientific community. PMID:27057765

  17. Antileishmanial lead structures from nature: analysis of structure-activity relationships of a compound library derived from caffeic Acid bornyl ester.

    PubMed

    Glaser, Jan; Schultheis, Martina; Hazra, Sudipta; Hazra, Banasri; Moll, Heidrun; Schurigt, Uta; Holzgrabe, Ulrike

    2014-01-01

    Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC50 = 48.8 µM). To investigate the structure-activity relationship (SAR), a library of compounds based on 1 was synthesized and tested in vitro against L. major and L. donovani promastigotes, and L. major amastigotes. Cytotoxicity was determined using a murine J774.1 cell line and bone marrow derived macrophages (BMDM). Some compounds showed antileishmanial activity in the concentration range of pentamidine and miltefosine which are the standard drugs in use. In the L. major amastigote assay compounds 15, 19 and 20 showed good activity with relatively low cytotoxicity against BMDM, resulting in acceptable selectivity indices. Molecules with adjacent phenolic hydroxyl groups exhibited elevated cytotoxicity against murine cell lines J774.1 and BMDM. The Michael system seems not to be essential for antileishmanial activity. Based on the results compound 27 can be regarded as new lead structure for further structure optimization. PMID:24473204

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

    PubMed

    Tropak, Michael B; Mahuran, Don

    2007-10-01

    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 beta-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 beta-hexosaminidase inhibitors (low microm IC50) increased mutant enzyme levels to >or= 10% in chronic Tay-Sachs fibroblasts and also attenuated the thermo-denaturation of beta-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 noncarbohydrate-based beta-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 beta-hexosaminidase pharmacological chaperone and compared favorably with our best carbohydrate-based pharmacological chaperone in patient cells with various mutant genotypes. PMID:17894780

  19. Comprehensive identification of active compounds in tablets by flow-injection data-dependent tandem mass spectrometry combined with library search.

    PubMed

    Pavlic, Marion; Schubert, Birthe; Libiseller, Kathrin; Oberacher, Herbert

    2010-04-15

    A convenient mass spectrometric approach for the identification of toxicologically relevant compounds in tablets and tablet residues is presented. For comprehensive forensic-toxicological analysis electrospray ionization mass spectrometry was accomplished in positive as well as in negative ion mode on a quadrupole-quadrupole-time-of-flight instrument. Dissolved samples were introduced into the mass spectrometer by flow-injection. Mass spectra as well as tandem mass spectra were acquired. A data-dependent acquisition strategy was used to switch between the mass spectrometric modes. Identification was accomplished via search within a tandem mass spectral library. The applied database contained 8252 spectra collected from 836 compounds in positive ion mode as well as 1023 spectra collected from 103 compounds in negative ion mode. A total of 22 casework samples collected during autopsies from mouth, oesophagus or gastric contents, seized by the police, or found with patients at hospital were screened. Twelve samples contained compounds only detectable in positive ion mode (sildenafil, dihydrocodeine, diphenhydramine, oxprenolol, N-methyl-3,4-methylenedioxyamphetamine, morphine, amphetamine, caffeine, pemoline, orphenadrine, m-chlorphenylpiperazine and tramadol), six samples contained species exclusively detectable in negative ion mode (salicylic acid, acetylsalicylic acid, ibuprofen, ketorolac, valproic acid and phenobarbital), and three samples contained diclofenac detectable in both ionization polarities. One sample did not contain any compound amenable to mass spectrometric analysis. For verification all samples were additionally analyzed by GC/MS. Both methods revealed identical results for all but one sample. The beta-adrenergic blocker oxprenolol was exclusively detected by the flow-injection method. PMID:20097023

  20. Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds

    PubMed Central

    Johnson, Alex; Elya, Carolyn; Anderson, Johanna; Clark, Julie; Connelly, Michele; Yang, Lei; Min, Jaeki; Sato, Yuko; Guy, R. Kiplin; Landfear, Scott M.

    2015-01-01

    Development of resistance against current antimalarial drugs necessitates the search for novel drugs that interact with different targets and have distinct mechanisms of action. Malaria parasites depend upon high levels of glucose uptake followed by inefficient metabolic utilization via the glycolytic pathway, and the Plasmodium falciparum hexose transporter PfHT, which mediates uptake of glucose, has thus been recognized as a promising drug target. This transporter is highly divergent from mammalian hexose transporters, and it appears to be a permease that is essential for parasite viability in intra-erythrocytic, mosquito, and liver stages of the parasite life cycle. An assay was developed that is appropriate for high throughput screening against PfHT based upon heterologous expression of PfHT in Leishmania mexicana parasites that are null mutants for their endogenous hexose transporters. Screening of two focused libraries of antimalarial compounds identified two such compounds that are high potency selective inhibitors of PfHT compared to human GLUT1. Additionally, 7 other compounds were identified that are lower potency and lower specificity PfHT inhibitors but might nonetheless serve as starting points for identification of analogs with more selective properties. These results further support the potential of PfHT as a novel drug target. PMID:25894322

  1. 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, "LJ" launched…

  2. 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

  3. High-Throughput Sorting and Placement of One-Bead-One-Compound (OBOC) Libraries from Bulk to Single Wells in Organic Solvent

    PubMed Central

    Bordo, Mark W.; Oketokoun, Rafiou; Cross, Conor J.; Bao, Kai; Lee, Jeong Heon; Feygin, Ilya; Chang, Alex B.; Frangioni, John V.; Choi, Hak Soo

    2015-01-01

    One-bead-one-compound (OBOC) solid-phase combinatorial chemistry has been used extensively in drug discovery. However, a major bottleneck has been the sorting of individual beads, while still swollen in organic solvent, into individual wells of a microwell plate. To solve this problem we have constructed an automated bead sorting system with integrated quality control that is capable of sorting and placing large numbers of beads in bulk to single wells of a 384-well plate, all in organic solvent. The bead sorter employs a unique, reciprocating fluidic design capable of depositing 1 bead per 1.5 s with an average accuracy of 97%. We quantified the performance of this instrument by sorting over 8,500 beads followed by cleaving the conjugated compound and confirming the chemical identity of each by LC/MS. This instrument should enable more efficient screening of combinatorial small molecule libraries without the need to dry beads or otherwise change chemical environment. PMID:25879633

  4. Comparison of (bio-)transformation methods for the generation of metabolite-like compound libraries of p38α MAP kinase inhibitors using high-resolution screening.

    PubMed

    Falck, David; Rahimi Pirkolachachi, Fatie; Giera, Martin; Honing, Maarten; Kool, Jeroen; Niessen, Wilfried M A

    2014-01-01

    Four hydrophobic p38α mitogen-activated protein kinase inhibitors were refluxed with 7.5% hydrogen peroxide at 80°C and irradiated with visible light in order to generate more hydrophilic conversion products. The resulting mixtures were analyzed in a high-resolution screening (HRS) platform, featuring liquid chromatographic separation coupled in parallel with a fluorescence enhancement based continuous-flow affinity bioassay towards the p38α mitogen-activated protein kinase and with high-resolution (tandem) mass spectrometry on an ion-trap-time-of-flight hybrid instrument. The results were compared with similar data where chemical diversity was achieved by means of electrochemical conversion or incubation with either human liver microsomes or cytochrome P450s from Bacillus megaterium (BM3s). In total, more than 50 conversion products were identified. The metabolite-like compound libraries studied are discussed in terms of the reactions enabled, the retention of affinity, and the change in hydrophilicity by modification, in summary the ability to generate bioactive, more hydrophilic potential lead compounds. In this context, HRS is demonstrated to be an effective tool as it reduces the effort directed towards laborious synthesis and purification schemes. PMID:24090642

  5. Expression and purification of human mPGES-1 in E. coli and identification of inhibitory compounds from a drug-library.

    PubMed

    Kim, Woo-Il; Choi, Kyung-A; Do, Hyun-Soo; Yu, Yeon Gyu

    2008-11-30

    Human microsomal prostaglandin E synthase-1 (mPGES-1) is a membrane associated protein that catalyzes the conversion of prostaglandin H(2) (PGH(2)) into prostaglandin E(2) (PGE(2)). In this study, the expression of human mPGES-1 in E. coli was significantly enhanced by modifying the utility of specific codons and the recombinant mPGES-1 was efficiently purified to homogeneity. The K(m) and V(max) of the purified enzyme were determined and the trimeric state characterized by chemical cross-linking with glutaraldehyde. The purified mPGES-1 was used for the screening of a chemical library of bioactive or drug compounds to identify novel inhibitors, and oxacillin and dyphylline were identified as moderately inhibiting mPGES-1 with IC(50) values of 100 and 200 microM, respectively. As these compounds competitively inhibited the catalysis of PGH(2), their binding sites appeared to be located near the PGH2 binding pocket. PMID:19017494

  6. Quantum efficiency and bandgap analysis for combinatorial photovoltaics: sorting activity of Cu-O compounds in all-oxide device libraries.

    PubMed

    Anderson, Assaf Y; Bouhadana, Yaniv; Barad, Hannah-Noa; Kupfer, Benjamin; Rosh-Hodesh, Eli; Aviv, Hagit; Tischler, Yaakov R; Rühle, Sven; Zaban, Arie

    2014-02-10

    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

  7. 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

  8. An FDA-Drug Library Screen for Compounds with Bioactivities against Meticillin-Resistant Staphylococcus aureus (MRSA)

    PubMed Central

    Lau, Qiu Ying; Tan, Yoke Yan Fion; Goh, Vanessa Chai Yin; Lee, David Jing Qin; Ng, Fui Mee; Ong, Esther H. Q.; Hill, Jeffrey; Chia, Cheng San Brian

    2015-01-01

    The lack of new antibacterial drugs entering the market and their misuse have resulted in the emergence of drug-resistant bacteria, posing a major health crisis worldwide. In particular, meticillin-resistant Staphylococcus aureus (MRSA), a pathogen responsible for numerous human infections, has become endemic in hospitals worldwide. Drug repurposing, the finding of new therapeutic indications for approved drugs, is deemed a plausible solution to accelerate drug discovery and development in this area. Towards this end, we screened 1163 drugs approved by the Food and Drug Administration (FDA) for bioactivities against MRSA in a 10 μM single-point assay. After excluding known antibiotics and antiseptics, six compounds were identified and their MICs were determined against a panel of clinical MRSA strains. A toxicity assay using human keratinocytes was also conducted to gauge their potential for repurposing as topical agents for treating MRSA skin infections. PMID:27025633

  9. Combined Use of Oligopeptides, Fragment Libraries, and Natural Compounds: A Comprehensive Approach To Sample the Druggability of Vascular Endothelial Growth Factor.

    PubMed

    Bayó-Puxan, Núria; Rodríguez-Mias, Ricard; Goldflam, Michael; Kotev, Martin; Ciudad, Sonia; Hipolito, Christopher J; Varese, Monica; Suga, Hiroaki; Campos-Olivas, Ramón; Barril, Xavier; Guallar, Víctor; Teixidó, Meritxell; García, Jesús; Giralt, Ernest

    2016-04-19

    The modulation of protein-protein interactions (PPIs) is emerging as a highly promising tool to fight diseases. However, whereas an increasing number of compounds are able to disrupt peptide-mediated PPIs efficiently, the inhibition of domain-domain PPIs appears to be much more challenging. Herein, we report our results related to the interaction between vascular endothelial growth factor (VEGF) and its receptor (VEGFR). The VEGF-VEGFR interaction is a typical domain-domain PPI that is highly relevant for the treatment of cancer and some retinopathies. Our final goal was to identify ligands able to bind VEGF at the region used by the growth factor to interact with its receptor. We undertook an extensive study, combining a variety of experimental approaches, including NMR-spectroscopy-based screening of small organic fragments, peptide libraries, and medicinal plant extracts. The key feature of the successful ligands that emerged from this study was their capacity to expose hydrophobic functional groups able to interact with the hydrophobic hot spots at the interacting VEGF surface patch. PMID:26553526

  10. Library Cooperation.

    ERIC Educational Resources Information Center

    Lund, Patricia; And Others

    1993-01-01

    Includes nine articles that discuss cooperative library networking in Illinois. Highlights include library systems as cooperative agencies; PALI (Private Academic Libraries of Illinois); rural school and public library development; systemwide users; regional medical libraries; virtual libraries and the Coalition for Networked Information; a…

  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. [Review of digital ground object spectral library].

    PubMed

    Zhou, Xiao-Hu; Zhou, Ding-Wu

    2009-06-01

    A higher spectral resolution is the main direction of developing remote sensing technology, and it is quite important to set up the digital ground object reflectance spectral database library, one of fundamental research fields in remote sensing application. Remote sensing application has been increasingly relying on ground object spectral characteristics, and quantitative analysis has been developed to a new stage. The present article summarized and systematically introduced the research status quo and development trend of digital ground object reflectance spectral libraries at home and in the world in recent years. Introducing the spectral libraries has been established, including desertification spectral database library, plants spectral database library, geological spectral database library, soil spectral database library, minerals spectral database library, cloud spectral database library, snow spectral database library, the atmosphere spectral database library, rocks spectral database library, water spectral database library, meteorites spectral database library, moon rock spectral database library, and man-made materials spectral database library, mixture spectral database library, volatile compounds spectral database library, and liquids spectral database library. In the process of establishing spectral database libraries, there have been some problems, such as the lack of uniform national spectral database standard and uniform standards for the ground object features as well as the comparability between different databases. In addition, data sharing mechanism can not be carried out, etc. This article also put forward some suggestions on those problems. PMID:19810544

  13. 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)

  14. Synthesis of Diverse (11)C-Labeled PET Radiotracers via Direct Incorporation of [(11)C]CO2.

    PubMed

    Mossine, Andrew V; Brooks, Allen F; Jackson, Isaac M; Quesada, Carole A; Sherman, Phillip; Cole, Erin L; Donnelly, David J; Scott, Peter J H; Shao, Xia

    2016-05-18

    Three new positron emission tomography (PET) radiotracers of interest to our functional neuroimaging and translational oncology programs have been prepared through new developments in [(11)C]CO2 fixation chemistry. [(11)C]QZ (glutaminyl cyclase) was prepared via a tandem trapping of [(11)C]CO2/intramolecular cyclization; [(11)C]tideglusib (glycogen synthase kinase-3) was synthesized through a tandem trapping of [(11)C]CO2 followed by an intermolecular cycloaddition between a [(11)C]isocyanate and an isothiocyanate to form the 1,2,4-thiadiazolidine-3,5-dione core; [(11)C]ibrutinib (Bruton's tyrosine kinase) was synthesized through a HATU peptide coupling of an amino precursor with [(11)C]acrylic acid (generated from [(11)C]CO2 fixation with vinylmagnesium bromide). All radiochemical syntheses are fully automated on commercial radiochemical synthesis modules and provide radiotracers in 1-5% radiochemical yield (noncorrected, based upon [(11)C]CO2). All three radiotracers have advanced to rodent imaging studies and preliminary PET imaging results are also reported. PMID:27043721

  15. 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;…

  16. 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

    2016-01-01

    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. PMID:26999101

  17. 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. PMID:25257911

  18. A Classification of Library and Information Science.

    ERIC Educational Resources Information Center

    Daniel, Ruth; And Others

    The language of library and information science is presented in a faceted library classification. To this vocabulary are added rules for combining terms into compound subjects; an overall linear order for all terms, elementary and compound; and a notation to maintain this order in a mechanical fashion. An extensive alphabetical index is included.…

  19. 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.

  20. 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,…

  1. 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 legislation…

  2. Library Advocacy

    ERIC Educational Resources Information Center

    Plunkett, Kate

    2010-01-01

    This paper is about the issue of advocacy. Standing at the vanguard of literacy, library media specialists have a unique role. However, it is time for media specialists to advocate their services in a proactive way. If library media specialists cannot, both individually and collectively, put advocacy at the forefront, then students will suffer the…

  3. Library Lighting.

    ERIC Educational Resources Information Center

    Metcalf, Keyes D.

    Chapter I provides a background and explains pertinent library lighting problems such as quality, function, aesthetics, intensity, and costs. Emphasis is on the quality and function of lighting for library users. Chapter II deals with the comments and answers to questions by persons who have a special interest and competence in the field of…

  4. Macintoshed Libraries.

    ERIC Educational Resources Information Center

    Valauskas, Edward J., Ed.; John, Nancy R., Ed.

    Contributed by librarians from public, academic, school, and special libraries, the 17 essays in this collection describe ways in which the Apple Macintosh is used in their libraries: (1) "Workstations and the Apple Macintosh" (Edward J. Valauskas); (2) "The Macintosh Experience at Chesapeake College" (Liz Cooper); (3) "ANSEL Character Set for the…

  5. 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…

  6. 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

  7. 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.

  8. 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)

  9. 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;…

  10. Standards for British Libraries.

    ERIC Educational Resources Information Center

    Vaughan, Anthony

    1982-01-01

    Reviews developments in British library standards since 1971, highlighting types of standards, public libraries, academic libraries (university, polytechnic, college), school libraries, and special libraries (hospital and health sciences, prison, subject specializations). Thirty-nine references are cited. (EJS)

  11. Expanding the potential of chiral chromatography for high-throughput screening of large compound libraries by means of sub-2μm Whelk-O 1 stationary phase in supercritical fluid conditions.

    PubMed

    Sciascera, Luca; Ismail, Omar; Ciogli, Alessia; Kotoni, Dorina; Cavazzini, Alberto; Botta, Lorenzo; Szczerba, Ted; Kocergin, Jelena; Villani, Claudio; Gasparrini, Francesco

    2015-02-27

    With the aim of exploring the potential of ultra-fast chiral chromatography for high-throughput analysis, the new sub-2 micron Whelk-O 1 chiral stationary phase (CSP) has been employed in supercritical fluid conditions to screen 129 racemates, mainly of pharmaceutical interest. By using a 5-cm long column (0.46cm internal diameter), a single co-solvent (MeOH) and a 7-min gradient elution, 85% of acidic and neutral analytes considered in this work have been successfully resolved, with resolution (Rs) larger than 2 in more than 65% of cases. Moreover, almost a half of basic samples that, for their own characteristics, are known to be difficult to separate on Whelk-O 1 CSP, have shown Rs greater than 0.3. The screening of the entire library could be accomplished in less than 24h (single run) with 63% of positive score. For well-resolved enantiomers (Rs roughly included between 1 and 3), we show that method transfer from gradient to isocratic conditions is straightforward. In many cases, isocratic ultra-fast separations (with analysis time smaller than 60s) have been achieved by simply employing, as isocratic mobile phase, the eluent composition at which the second enantiomer was eluted in gradient mode. By considering the extension and variety of the library in terms of chemico-physical and structural properties of compounds and numerousness, we believe that this work demonstrates the real potential of the technique for high-throughput enantioselective screening. PMID:25650355

  12. 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…

  13. Library Venturing.

    ERIC Educational Resources Information Center

    Wilson, H. Donald

    1986-01-01

    There is opportunity for service and profit to imaginative libraries organizing to provide new forms of knowledge. Librarians as entrepreneurs must learn venture management and finance. Available assistance includes growing entrepreneural understanding in large institutions; family and friends; private wealth-seeking investment; new business…

  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. Library Environment.

    ERIC Educational Resources Information Center

    Computers in Libraries, 1993

    1993-01-01

    This special section includes two articles that review products and services for the automated library environment. Highlights include ergonomic products; products for visually, hearing-, and speech-impaired users; analog film recorders; computer filters; document imaging systems; electric filing systems; and printers. A list of vendors is…

  16. Library Handbook.

    ERIC Educational Resources Information Center

    Cupp, Christian M., Ed.

    The purpose of this handbook is to help students, staff, and community patrons attain a reasonable degree of skill in using the Southeastern Community College Library effectively. The first section instructs the user on how to find information. A discussion of the card catalog and its use provides examples of catalog cards, reviews the…

  17. Library Automation and Library Education.

    ERIC Educational Resources Information Center

    Drabenstott, Jon, Ed.

    1987-01-01

    Several consultants address the issue of competencies required of professional librarians for the effective management of the automation process. Highlights include formal and professional ongoing education and the need for technical training and problem solving skills to enable librarians to evaluate and develop library systems effectively.…

  18. 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)

  19. 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)

  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. Library Instruction Assessment in Academic Libraries

    ERIC Educational Resources Information Center

    Tancheva, Kornelia; Andrews, Camille; Steinhart, Gail

    2007-01-01

    Determining the best methods of assessment for a library instruction program in a large research university can be a challenging task. Albert R. Mann Library at Cornell University Library has pilot-tested three methods of formative and summative assessment for its library instruction program--attitudinal, outcomes-based, and gap-measure--and…

  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. 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.

  4. 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

  5. Public Library in Thailand.

    ERIC Educational Resources Information Center

    Lerdsuriyakul, Kulthorn

    This paper on public libraries in Thailand begins with a section that provides background on public libraries in the past, lists the functions of the public library, and describes three size classifications of public libraries. The second section outlines the tasks of the current public library in three areas: informal education; nonformal…

  6. 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…

  7. Library Services. Miscellaneous Papers.

    ERIC Educational Resources Information Center

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

    Papers on library journal cooperation, interlibrary lending, library services to minorities, and school library media centers, which were presented at the 1983 International Federation of Library Associations (IFLA) conference, include: (1) "The Co-operation between Editors of Library Journals in Socialist Countries," in which Wolfgang Korluss…

  8. 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)

  9. 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,…

  10. Library Research and Statistics.

    ERIC Educational Resources Information Center

    Lynch, Mary Jo; Brier, David J.; Lebbin, Vickery K.; Halstead, Kent; Fox, Bette-Lee; Kremen, Maya L.; Miller, Marilyn L.; Shontz, Marilyn L.

    1998-01-01

    Provides nine articles: research on libraries and librarianship, 1997; changing faces of library education (ALA-accredited graduate program title changes); number of libraries in the U.S., Canada, and Mexico; highlights of NCES surveys; library acquisition expenditures; price indexes for public and academic libraries; state rankings of selected…

  11. 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)

  12. The Library of Virginia's Digital Library Project.

    ERIC Educational Resources Information Center

    Roderick, Elizabeth; Taylor, Jean Marie; Byrd, Sam; Courson, Glenn

    1997-01-01

    Describes The Library of Virginia's Digital Library Project that has made many of its state library collections available via the Internet and World Wide Web. Highlights include digitization decisions; the HTML Web gateway; the online catalog; microfilm digitization; users and use statistics; and future projects. (LRW)

  13. Synthesis of a sulfahydantoin library.

    PubMed

    Albericio, F; Bryman, L M; Garcia, J; Michelotti, E L; Nicolás, E; Tice, C M

    2001-01-01

    A five-step solid-phase synthesis of sulfahydantoins from alpha-amino acids and aldehydes was developed. The synthetic method allows the use of hindered amino acids, including Val, Phg, and Aib, and use of aromatic aldehydes substituted with electron-withdrawing and -donating groups. Some limitations were encountered with amino acids with reactive side chains. A small but diverse library of compounds was produced for biological testing. PMID:11350253

  14. Alabama Public Library Service Library Directory and 1996 Statistical Report.

    ERIC Educational Resources Information Center

    Alabama Public Library Service, Montgomery.

    This publication presents library contact information and statistics for Alabama public libraries for fiscal year 1996 (October 1, 1995-September 30, 1996). The library directory is arranged by type of library: public libraries, single-county public library systems, multi-county public library systems, and multitype library systems. Entries…

  15. Conservation of Library Materials.

    ERIC Educational Resources Information Center

    Illinois Libraries, 1985

    1985-01-01

    Twelve articles cover books as artifacts; workstations for conservation of library materials; care of scrapbooks, albums, and photographs; map preservation; library environment; flood recovery; disaster prevention and preparedness; incorporating preservation into library organization; and bibliography of Chester Public Library (Illinois) First…

  16. The Bush Memorial Library.

    ERIC Educational Resources Information Center

    Hamline University Bulletin, 1971

    1971-01-01

    The Bush Memorial Library was formally dedicated on October 9, 1971. As part of Hamline University in St. Paul, Minnesota, the Bush Memorial Library has a reading room, audio booths, and audio-visual classroom as well as an audio control room. The Bush Memorial Library is a member of the Cooperating Libraries in Consortium which is a cooperative…

  17. 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…

  18. 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…

  19. 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…

  20. 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…

  1. The Library Building Tomorrow.

    ERIC Educational Resources Information Center

    Waters, Richard L.

    1987-01-01

    Examination of the library of tomorrow speculates about the impact of changes in the functions of government, technology, demographics, lifestyle, and values on the role of the library. A facility for the contemporary public library is described that can both accommodate traditional services and respond to changes in the library's role. (17…

  2. School Libraries in Hawaii.

    ERIC Educational Resources Information Center

    Bard, Therese Bissen

    This paper outlines the history, functions, administration, and current focus of school library services in Hawaii, which is the only state in the United States with a library staffed by a trained librarian in every public school. Its first school library was established in 1882. Elementary school libraries developed concurrently with secondary…

  3. 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…

  4. Economics of Academic Libraries.

    ERIC Educational Resources Information Center

    Baumol, William J.; Marcus, Matityahu

    An analysis is conducted of economic issues pertinent to library planning in higher education in the face of rising costs and diminishing financial support. The individual chapters deal with: 1) growth rates in large university libraries; 2) library costs in colleges and universities; 3) cost trends and long-range plans; 4) library data; and 5) a…

  5. Alaska Library Directory, 1996.

    ERIC Educational Resources Information Center

    Jennings, Mary, Ed.

    This directory of Alaska's Libraries lists: members of the Alaska Library Association (AkLA) Executive Council and Committee Chairs; State Board of Education members; members of the Governor's Advisory Council on Libraries; school, academic and public libraries and their addresses, phone and fax numbers, and contact persons; personal,…

  6. Comparison of the Pharmacokinetics of Different Analogs of 11C-Labeled TZTP for Imaging Muscarinic M2 Receptors with PET

    PubMed Central

    Reid, Alicia E.; Ding, Yu-Shin; Eckelman, William C.; Logan, Jean; Alexoff, David; Shea, Colleen; Xu, Youwen; Fowler, Joanna S.

    2011-01-01

    Introduction The only radiotracer available for the selective imaging of muscarinic M2 receptors in vivo is 3-(3-{3-[18F]fluoropropyl)thio}-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine) ([18F]FP-TZTP). We have prepared and labeled FP-TZTP and two other TZTP derivatives with 11C at the methylpyridine moiety to explore the potential of using C-11 labeled FP-TZTP for PET imaging of M2 receptors and to compare the effect of small structural changes on tracer pharmacokinetics (PK) in brain and peripheral organs. Methods 11C radiolabeled [FP-TZTP, 3], 3-(3-propyl)-TZTP [P-TZTP, 6], 3,3,3-(3-(3-trifluoropropyl)-TZTP [F3P-TZTP, 10] were prepared and log D, plasma protein binding (PPB), affinity constants, time-activity curves (TACs), area under the curve (AUC) for arterial plasma, distribution volumes (DV) and pharmacological blockade in baboons were compared. Results Values for log D, PPB and affinity constants were similar for 3, 6 and 10. The fraction of parent radiotracer in the plasma was higher and the AUC lower for 10 than for 3 and 6. TACs for brain regions were similar for 3 and 6, which showed PK similar to the F-18 tracer, while 10 showed slower uptake and little clearance over 90 min. DV’s for 3 and 6 were similar to the F-18 tracer but higher for 10. Uptake of the three tracers was significantly reduced by coinjection of unlabeled 3 and 6. Conclusion Small structural variations on the TZTP structure greatly altered the PK in brain and behavior in blood with little change in the log D, PPB or affinity. The study suggests that 11C radiolabeled 3 will be a suitable alternative to [18F]FP-TZTP for translational studies in humans. PMID:18355684

  7. 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

    2016-06-01

    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. PMID:27198617

  8. 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…

  9. 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. PMID:27009852

  10. 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. PMID:27053324

  11. Drug target identification using a trypanosome overexpression library.

    PubMed

    Begolo, Daniela; Erben, Esteban; Clayton, Christine

    2014-10-01

    Elucidation of molecular targets is very important for lead optimization during the drug development process. We describe a direct method to find targets of antitrypanosomal compounds against Trypanosoma brucei using a trypanosome overexpression library. As proof of concept, we treated the library with difluoromethylornithine and DDD85646 and identified their respective targets, ornithine decarboxylase and N-myristoyltransferase. The overexpression library could be a useful tool to study the modes of action of novel antitrypanosomal drug candidates. PMID:25049244

  12. 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" by Michael Rinehart…

  13. The Libraries of Rio.

    ERIC Educational Resources Information Center

    Foster, Barbara

    1988-01-01

    Describes aspects of several libraries in Rio de Janeiro. Topics covered include library policies, budgets, periodicals and books in the collections, classification schemes used, and literary areas of interest to patrons. (6 references) (CLB)

  14. 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)

  15. 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)

  16. Medical Library Association

    MedlinePlus

    ... 11th, 2016 Patricia Flatley Brennan, registered nurse, informatician, industrial engineer, and renowned researcher is appointed as Director of the National Library of Medicine Tweets Copyright © 2016 Medical Library Association. ...

  17. Facility Focus: Libraries.

    ERIC Educational Resources Information Center

    College Planning & Management, 2003

    2003-01-01

    Describes the designs of the Ferris State University Library for Information, Technology and Education (FLITE), and the Meyer Library and Information Technology Center at Southwest Missouri State University. Includes photographs. (EV)

  18. International School Library Day.

    ERIC Educational Resources Information Center

    Clyde, Laurel A.

    2001-01-01

    Describes the development of an International School Library Day and discusses activities in Australian school libraries. Highlights include the development of Web pages; sponsorship by national, state, or provincial associations; publicity materials; joint activities with other countries; student involvement; and activities with public libraries.…

  19. The Toy Lending Library.

    ERIC Educational Resources Information Center

    Wiscont, Jeanne Mull

    This paper explores the concept of toy lending libraries. The first six chapters discuss: (1) the history of toy lending libraries; (2) the values and purposes of using games and toys with children; (2) the contribution of games and toys to the goals of a children's services library division; (3) examples of toy lending service in public…

  20. 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 systems,…

  1. 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…

  2. Simple Library Bookkeeping.

    ERIC Educational Resources Information Center

    Hoffman, Herbert H.

    A simple and cheap manual double entry continuous transaction posting system with running balances is developed for bookkeeping by small libraries. A very small library may operate without any system of fiscal control but when a library's budget approaches three figures, some kind of bookkeeping must be introduced. To maintain control over his…

  3. Library Awareness Survey.

    ERIC Educational Resources Information Center

    Rice, James

    1992-01-01

    Reports results of a survey of Iowa City residents regarding their awareness of public library services. Data are presented on use of the library for factual information, statistical/numerical information, learning, and information not available at home; awareness of in-person and telephone library reference services; and knowledge about…

  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. Environmental Library Systems

    ERIC Educational Resources Information Center

    Thomas, Sarah M.; Needle, Lester P.

    1975-01-01

    The U. S. Environmental Protection Agency (EPA) Library System consists of 28 libraries. The libraries are supported by computer systems covering journal and book holdings, journal check-in, circulation, document control, EPA reports, international exchange items, and specialized subject area collections. (Author)

  6. Bookmarking Your Library's Teens.

    ERIC Educational Resources Information Center

    Williams, Mary Pasek

    1999-01-01

    Describes one public library's project of photographing teenagers reading around the library and making the photos into bookmarks with the library logo and a "read" message. Discusses the background, arrangements, photo session, assembly, distribution and publicity, and funding and community response. (AEF)

  7. The End of Libraries.

    ERIC Educational Resources Information Center

    Thompson, James

    1983-01-01

    Suggests that if librarians and libraries are to continue to fulfill their true tasks, they need to adapt to changes resulting from new technology and overcome the professional paralysis that has made most major libraries largely unusable. Problems of size, arrangement, and catalogs are identified as contributors to unusable library. (EJS)

  8. 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…

  9. 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)

  10. 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.…

  11. 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 as…

  12. A Library That Swings

    ERIC Educational Resources Information Center

    Spragens, Thomas A.

    1971-01-01

    The Grace Doherty Library (Centre College, Danville, Kentucky) is a library that "swings," being so designed that a substantial part of its space is used alternately for classroom purposes during the day and for library reading-study space in the peak evening hours. (Author)

  13. School Libraries in Fiji.

    ERIC Educational Resources Information Center

    Singh, Harry

    1995-01-01

    Presents a 50-year history of school library development and national educational programs in Fiji and discusses the future of Fiji's elementary and secondary school libraries. Examines obstacles to school library development including government ignorance, lack of trained librarians, changes in school curriculum, lack of financing, and high costs…

  14. 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…

  15. 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…

  16. 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)

  17. 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)

  18. 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…

  19. 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…

  20. 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…

  1. Automation in Libraries.

    ERIC Educational Resources Information Center

    Canadian Library Association, Ottawa (Ontario).

    The fourth Canadian Association of College and University Libraries (CACUL) Conference on Library Automation was held in Hamilton, June 20-21, 1970, as a pre-conference workshop of the Canadian Library Association (CLA). The purpose of the conference was to present papers on current projects and to discuss the continuing need for this type of…

  2. 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…

  3. Staffing the College Library

    ERIC Educational Resources Information Center

    Thomas, Bruce

    1973-01-01

    College libraries use a variety of methods to identify and select professional library personnel. 70 libraries responded to a questionnaire about their methods and the results are presented. The effectiveness of advertisements, employment services, testing and reference checks are among the topics discussed. (DH)

  4. 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…

  5. 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…

  6. 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…

  7. 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…

  8. The Honor System Library

    ERIC Educational Resources Information Center

    Marie, Kristen L.

    2005-01-01

    An honor system library can be created inside the library media center (LMC). Where students can access free books and magazines that require no formal checkouts. The honor library system at Washington High School, Fremont, California, has become self-sustaining. As many students, parents and teachers donate quality material. No student is ever…

  9. Libraries in Africa.

    ERIC Educational Resources Information Center

    Enyia, Christian O.; And Others

    1991-01-01

    Includes five articles that discuss library and information work in Africa. Highlights include computerization in Nigerian libraries; education for library and information services in Ghana; an evaluation of African librarianship; the role of Nigerian publishers in national development; and the role of information services in national development…

  10. Rhode Island Library Trustees Manual.

    ERIC Educational Resources Information Center

    Iacono, Frank P., Ed.

    This handbook for library trustees identifies the duties and responsibilities of library boards and librarians, the qualifications of an effective library and of a library board, and library policy requirements. The concept of intellectual freedom, the Library Bill of Rights, and the Freedom to Read Statement are discussed, and the role of the…

  11. Planning & Urban Affairs Library Manual.

    ERIC Educational Resources Information Center

    Knobbe, Mary L., Ed.; Lessel, Janice W., Ed.

    Written especially for persons without a library degree who are operating a small urban study or planning agency library on a part-time basis. Subjects covered are: (1) library function and staff function, duties and training; (2) physical layout and equipment of library; (3) establishing and maintaining the library; (4) library administration;…

  12. 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.

  13. 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…

  14. 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

  15. 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…

  16. Uniqueness: skews bit occurrence frequencies in randomly generated fingerprint libraries.

    PubMed

    Chen, Nelson G

    2016-08-01

    Requiring that randomly generated chemical fingerprint libraries have unique fingerprints such that no two fingerprints are identical causes a systematic skew in bit occurrence frequencies, the proportion at which specified bits are set. Observed frequencies (O) at which each bit is set within the resulting libraries systematically differ from frequencies at which bits are set at fingerprint generation (E). Observed frequencies systematically skew toward 0.5, with the effect being more pronounced as library size approaches the compound space, which is the total number of unique possible fingerprints given the number of bit positions each fingerprint contains. The effect is quantified for varying library sizes as a fraction of the overall compound space, and for changes in the specified frequency E. The cause and implications for this systematic skew are subsequently discussed. When generating random libraries of chemical fingerprints, the imposition of a uniqueness requirement should either be avoided or taken into account. PMID:27230477

  17. 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.

  18. 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. PMID:27311891

  19. 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.

  20. 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.

  1. Malta: The Library Scene and its Setting

    ERIC Educational Resources Information Center

    Biggs, P. T.

    1973-01-01

    The cultural background of Malta is briefly analyzed as it relates to library service on the island. The library system includes public libraries, university libraries, religious libraries and special libraries. (39 references) (DH)

  2. Chemical Biology Probes from Advanced DNA-encoded Libraries.

    PubMed

    Salamon, Hazem; Klika Škopić, Mateja; Jung, Kathrin; Bugain, Olivia; Brunschweiger, Andreas

    2016-02-19

    The identification of bioactive compounds is a crucial step toward development of probes for chemical biology studies. Screening of DNA-encoded small molecule libraries (DELs) has emerged as a validated technology to interrogate vast chemical space. DELs consist of chimeric molecules composed of a low-molecular weight compound that is conjugated to a DNA identifier tag. They are screened as pooled libraries using selection to identify "hits." Screening of DELs has identified numerous bioactive compounds. Some of these molecules were instrumental in gaining a deeper understanding of biological systems. One of the main challenges in the field is the development of synthesis methodology for DELs. PMID:26820267

  3. 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…

  4. 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.

  5. 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…

  6. Resources of North Carolina Libraries.

    ERIC Educational Resources Information Center

    Downs, Robert B., Ed.

    The conclusion of the survey is that North Carolina libraries do not have sufficient resources, physical facilities or staff to provide adequate library service for the state. The survey covers the present and potential roles of the State Library, the State Department of Archives and History, public libraries, university libraries, senior and…

  7. 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…

  8. Computer Based Library Orientation.

    ERIC Educational Resources Information Center

    Machalow, Robert

    This document presents computer-based lessons used to teach basic library skills to college students at York College of the City University of New York. The information for library orientation has been entered on a disk which must be used in conjunction with a word processing program, the Applewriter IIe, and an Apple IIe microcomputer. The…

  9. 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. Cooke, Finger…

  10. Libraries: Drawn to Knowledge.

    ERIC Educational Resources Information Center

    Havens, Kevin

    2003-01-01

    Discusses how to make a college library the center of campus activity, explaining how to find the proper balance of technology and tradition (e.g., harnessing new media to teach critical thinking skills, having library staff assume primary responsibility for providing information literacy training, training students to use print as well as…

  11. 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,…

  12. Library Resources Workbook, Revised.

    ERIC Educational Resources Information Center

    Phillips, Dennis

    Intended to provide a basic overview of the facilities and resources of the library on the Allentown Campus of Pennsylvania State University, this student workbook is designed to familiarize students with what is available to them in the library; to introduce them to skills likely to be used in varying degrees throughout life, regardless of what…

  13. 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…

  14. 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.…

  15. 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."

  16. 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)

  17. 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 sections:…

  18. 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…

  19. 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…

  20. 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)

  1. 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…

  2. Libraries and Adult Learners.

    ERIC Educational Resources Information Center

    Josey, E. J., Ed.

    1982-01-01

    Of the 13 essays presented in this special issue on libraries and adult education, 8 focus on programs and services from the public library for adult learners. These essays provide information on: (1) an Education Information Centers Program (EIC) designed to complement employment skills training provided under the Comprehensive Employment and…

  3. 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 Web" (Theo van…

  4. Idaho's Library Future.

    ERIC Educational Resources Information Center

    Idaho State Library, Boise.

    In l998, Idahoans gathered in a series of six Regional Futures Conferences to identify what they thought was probable during the next ten years, what was possible for libraries to do and be, and what a preferred future of Idaho libraries might be. Participants from the regional conferences then convened to refine and focus descriptions of the…

  5. 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…

  6. Using Your Library Effectively.

    ERIC Educational Resources Information Center

    Hennepin County Library, Minnetonka, MN.

    This collection of materials for a three-hour instructional program for young people and adults in the effective use of the public library includes an introduction to the program, a teaching guide for the librarian, a packet of materials for students, and a summary of 90 evaluations of the program as it was presented at two area libraries and…

  7. 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…

  8. 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.

  9. 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.

  10. 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…

  11. 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…

  12. 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…

  13. 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.…

  14. "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…

  15. 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…

  16. Library Automation Style Guide.

    ERIC Educational Resources Information Center

    Gaylord Bros., Liverpool, NY.

    This library automation style guide lists specific terms and names often used in the library automation industry. The terms and/or acronyms are listed alphabetically and each is followed by a brief definition. The guide refers to the "Chicago Manual of Style" for general rules, and a notes section is included for the convenience of individual…

  17. Hospital Library Administration.

    ERIC Educational Resources Information Center

    Cramer, Anne

    The objectives of a hospital are to improve patient care, while the objectives of a hospital library are to improve services to the staff which will support their efforts. This handbook dealing with hospital administration is designed to aid the librarian in either implementing a hospital library, or improving services in an existing medical…

  18. Ubibliotheca The Spiral Library.

    ERIC Educational Resources Information Center

    Ottewell, Guy

    A plan for a library with a storage level in the shape of a flat spiral is presented. The advantages of such a plan include: space saving, easy expansion of the building, an unbroken sequence of shelving, quick access to all books and freedom in the design of the library's other sectors. This plan is especially suited for the research library…

  19. University Libraries in Transition.

    ERIC Educational Resources Information Center

    Hyatt, James A.

    1986-01-01

    College and university libraries are experiencing change in the ways they provide services and in their responses to rising costs and reduced financial support. These conditions result from three major phenomena: the information explosion, the technology revolution, and escalating library costs. (MLW)

  20. Facility Focus: Libraries.

    ERIC Educational Resources Information Center

    College Planning & Management, 1997

    1997-01-01

    Describes four operating libraries located at Union Theological Seminary in Virginia, Emory University in Georgia, Kean College in New Jersey, and Community College of Philadelphia. Their size, cost, date completed, architect, and various features are provided. Despite technological advances, the college library is a feasible part of higher…

  1. Attribution of Library Costs

    ERIC Educational Resources Information Center

    Drake, Miriam A.

    1977-01-01

    Universities conduct a variety of cost-allocation studies that require the collection and analysis of the library cost-data. Cost accounting methods are used in most studies; however, costs are attributed to library user groups in a variety of ways. Cost accounting studies are reviewed and allocation methods are discussed. (Author)

  2. Maintaining Precious Library Resources.

    ERIC Educational Resources Information Center

    Wiens, Janet

    2002-01-01

    Using the examples of libraries at Southeast Missouri State University and the University of North Texas, discusses the big-picture approach and extensive communication among all users necessary for library maintenance efforts. Addresses establishing a master plan, prioritizing projects, having the right staff, and communicating. (EV)

  3. FRBR and School Libraries

    ERIC Educational Resources Information Center

    Hart, Amy

    2006-01-01

    This article discusses the Functional Requirements for Bibliographic Records (FRBR), a plan that is quickly gaining the support of library organizations around the globe. The FRBR Study Group was appointed by International Federation of Library Associations (IFLA) and issued its final report in 1998. The report redefines the basic unit of…

  4. 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…

  5. 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)

  6. 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…

  7. 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); and (5) "Using Technology: Spreadsheet…

  8. 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…

  9. Technion Libraries Systems Study.

    ERIC Educational Resources Information Center

    Thomas, Pauline

    This study is aimed at clarifying the objectives of the Technion Libraries' Systems, both within the Technion and as a national information resource, by defining the structure, organization, and methods to achieve these objectives. It considers Technion's future plans and current library practices as based on reports on the system, Technion…

  10. The Underground Library.

    ERIC Educational Resources Information Center

    American School and University, 1983

    1983-01-01

    Recessed 25 feet below grade, the library at the Lawrence Institute of Technology has a garden area below the light well. A large atrium with four skylights above the library serves as a buffer zone and an informal gathering place. (Author/MLF)