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PUBLICATIONS

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103 Total Publications
HOME | RESOURCES | Publications

PUBLICATIONS

103 Total Publications

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TITLES and AUTHORS Year Link PDF + Abstract
  • Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice Lemaire K, Ravier M A, Schraenen A, Creemers J W M, Van de Plas R, Granvik M, Van Lommel L, Waelkens

    Institution: Katholieke Universiteit Leuven

    Publication: PNAS vol. 106 no. 35: 14872–14877, doi: 10.1073/pnas.0906587106

    2009 abstract

    Zinc co-crystallizes with insulin in dense core secretory granules, but its role in insulin biosynthesis, storage and secretion is unknown. In this study we assessed the role of the zinc transporter ZnT8 using ZnT8-knockout (ZnT8−/−) mice. Absence of ZnT8 expression caused loss of zinc release upon stimulation of exocytosis, but normal rates of insulin biosynthesis, normal insulin content and preserved glucose-induced insulin release. Ultrastructurally, mature dense core insulin granules were rare in ZnT8−/− beta cells and were replaced by immature, pale insulin “progranules,” which were larger than in ZnT8+/+ islets. When mice were fed a control diet, glucose tolerance and insulin sensitivity were normal. However, after high-fat diet feeding, the ZnT8−/− mice became glucose intolerant or diabetic, and islets became less responsive to glucose. Our data show that the ZnT8 transporter is essential for the formation of insulin crystals in beta cells, contributing to the packaging efficiency of stored insulin. Interaction between the ZnT8−/− genotype and diet to induce diabetes is a model for further studies of the mechanism of disease of human ZNT8 gene mutations.

    Publication / Type:
    PNAS vol. 106 no. 35: 14872–14877, doi: 10.1073/pnas.0906587106
    Related Subject:
    Insulin zinc transporter ZnT8 glucose homeostasis mice
    Link:
    http://www.pnas.org/content/106/35/14872.abstract?tab=related
  • Identification of Novel Non-Hydroxamate Anthrax Toxin Lethal Factor Inhibitors by Topomeric Searching, Docking and Scoring, and In Vitro Screening Chiu T-L, Solberg J, Patil S, Geders T W, Zhang X, Rangarajan S, Francis R, Finzel B C, Walters M A,

    Institution: University of Minnesota

    Publication: J Chem Inf Model. 2009 December; 49(12): 2726–2734.  doi:  10.1021/ci900186w

    2009 abstract

    Anthrax is an infectious disease caused by Bacillus anthracis, a Gram-positive, rod-shaped, anaerobic bacterium. The lethal factor (LF) enzyme is secreted by B. anthracis as part of a tripartite exotoxin and is chiefly responsible for anthrax-related cytotoxicity. As LF can remain in the system long after antibiotics have eradicated B. anthracis from the body, the preferred therapeutic modality would be the administration of antibiotics together with an effective LF inhibitor. Although LF has garnered a great deal of attention as an attractive target for rational drug design, relatively few published inhibitors have demonstrated activity in cell-based assays and, to date, no LF inhibitor is available as a therapeutic or preventive agent. Here we present a novel in silico high-throughput virtual screening protocol that successfully identified 5 non-hydroxamic acid small molecules as new, preliminary LF inhibitor scaffolds with low micromolar inhibition against that target, resulting in a 12.8% experimental hit rate. This protocol screened approximately thirty-five million non-redundant compounds for potential activity against LF and comprised topomeric searching, docking and scoring, and drug-like filtering. Among these 5 hit compounds, none of which has previously been identified as a LF inhibitor, three exhibited experimental IC50 values less than 100 µM. These three preliminary hits may potentially serve as scaffolds for lead optimization, as well as templates for probe compounds to be used in mechanistic studies. Notably, our docking simulations predicted that these novel hits are likely to engage in critical ligand-receptor interactions with nearby residues in at least two of the three (S1’, S1–S2 and S2’) subsites in the LF substrate binding area. Further experimental characterization of these compounds is in process. We found that micromolar-level LF inhibition can be attained by compounds with non-hydroxamate zinc-binding groups that exhibit monodentate zinc chelation, as long as key hydrophobic interactions with at least two LF subsites are retained.

    Publication / Type:
    J Chem Inf Model. 2009 December; 49(12): 2726–2734.  doi:  10.1021/ci900186w
    Related Subject:
    Identification Novel Non-Hydroxamate Anthrax Toxin Lethal Factor Inhibitor Topomeric Docking Scoring In Vitro
    Link:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805240/
  • Validation of Low-Volume 1536-Well Assay-Ready Compound Plates Eriksson H, Brengdahl J, Sandström P, Rohman M, Becker B

    Institution: AstraZeneca and Tessela plc.

    Publication: J Biomol Screen June 2009 vol. 14 no. 5 468-475

    2009 abstract

    Assay-ready compound plates (ARPs) are sealed assay plates that contain DMSO solutions of screening compounds predispensed for particular assays. Assays are started by adding assay buffer and reagents to the ARPs. This concept offers important logistical advantages for screening such as decoupling of the plate preparation from the screening process and exchange of assay plates between different geographical locations. Compound solutions can be accurately and precisely dispensed by acoustic droplet ejection technology in the small volumes required for screening in the 1536-well format. At such low volumes, however, potential effects such as solvent evaporation, compound degradation, precipitation, or adsorption are reasons for concern with regard to assay reproducibility, performance, and shelf life of ARPs. To address these concerns, the authors screened freshly prepared ARPs using several types of assays. The results were compared to results obtained from plates stored for up to 13 days under 2 storage conditions (22 °C, —18 °C). Tight correlations between results were found that indicated that temperature and time had very little influence on the assay performance for up to about 1 week storage time of the plates. In addition, using a time series of microphotographs of DMSO droplets, the authors visually confirmed that the sizes of the droplets in ARPs apparently do not change over 13 days under certain storage conditions.

    Publication / Type:
    J Biomol Screen June 2009 vol. 14 no. 5 468-475
    Related Subject:
    Low-Volume 1536-Well Assay-Ready
    Link:
    http://jbx.sagepub.com/content/14/5/468.abstract
  • Innovation Leading the Way: Application of Lean Manufacturing to Sample Management Allen M, Wigglesworth M J

    Institution: GlaxoSmithKline

    Publication: Journal of Biomolecular Screening. 2009:515-522

    2009 abstract

    Historically, sample management successfully focused on providing compound quality and tracking distribution within a diverse geographic. However, if a competitive advantage is to be delivered in a changing environment of outsourcing, efficiency and customer service must now improve or face reconstruction. The authors have used discrete event simulation to model the compound process from chemistry to assay and applied lean manufacturing techniques to analyze and improve these processes. In doing so, they identified a value-adding process time of just 11 min within a procedure that took days. Modeling also allowed the analysis of equipment and human resources necessary to complete the expected demand in an acceptable cycle time. Layout and location of sample management and screening departments are key in allowing process integration, creating rapid flow of work, and delivering these efficiencies. Following this analysis and minor process changes, the authors have demonstrated for 2 programs that solid compounds can be converted to assay-ready plates in less than 4 h. In addition, it is now possible to deliver assay data from these compounds within the same working day, allowing chemistry teams more flexibility and more time to execute the next chemistry round. Additional application of lean manufacturing principles has the potential to further decrease cycle times while using fewer resources.

    Publication / Type:
    Journal of Biomolecular Screening. 2009:515-522
    Related Subject:
    Lean Manufacturing Sample
    Link:
    http://jbx.sagepub.com/content/14/5/515.abstract
  • Applications of Adaptive Focused Acoustics to Compound Management Nixon E, Holland-Crimmin S, Lupotsky B, Chan J, Curtis J, Dobbs K, Blaxill Z

    Institution: GlaxoSmithKline

    Publication: J Biomol Screen June 2009 vol. 14 no. 5 460-467

    2009 abstract

    Since the introduction of lithotripsy kidney stone therapy, Focused Acoustics and its properties have been thoroughly utilized in medicine and exploration. More recently, Compound Management is exploring its applications and benefits to sample integrity. There are 2 forms of Focused Acoustics: Acoustic Droplet Ejection and Adaptive Focused Acoustics, which work by emitting high-powered acoustic waves through water toward a focused point. This focused power results in noncontact plate-to-plate sample transfer or sample dissolution, respectively. For the purposes of this article, only Adaptive Focused Acoustics will be addressed. Adaptive Focused Acoustics uses high-powered acoustic waves to mix, homogenize, dissolve, and thaw samples. It facilitates transferable samples through noncontact, closed-container, isothermal mixing. Experimental results show significantly reduced mixing times, limited degradation, and ideal use for heat-sensitive compounds. Upon implementation, acoustic dissolution has reduced the number of samples requiring longer mixing times as well as reducing the number impacted by incomplete compound dissolution. It has also helped in increasing the overall sample concentration from 6 to 8 mM to 8 to 10 mM by ensuring complete compound solubilization. The application of Adaptive Focused Acoustics, however, cannot be applied to all Compound Management processes, such as sample thawing and low-volume sample reconstitution. This article will go on to describe the areas where Adaptive Focused Acoustics adds value as well as areas in which it has shown no clear benefit.

    Publication / Type:
    J Biomol Screen June 2009 vol. 14 no. 5 460-467
    Related Subject:
    Acoustics Compound
    Link:
    http://jbx.sagepub.com/content/14/5/460.abstract
  • Stability Through the Ages: The GSK Experience Blaxill Z, Holland-Crimmin S, Lifely R

    Institution: GlaxoSmithKline

    Publication: Journal of Biomolecular Screening 2009:547-556

    2009 abstract

    It is common knowledge in the pharmaceutical industry that the quality of a company's compound collection has a major influence on the success of biological screening in drug discovery programs. DMSO is the widely accepted solvent of choice for storage of compounds, despite the hygroscopic nature of the solvent, which can lead to stability issues. Other factors that can affect compound stability (e.g., degradation, precipitation) include concentration of compound, intrinsic compound stability, presence of reactive contaminants, storage format-related factors (vessel, sealing, etc.), storage conditions (temperature, humidity, freeze-thaw technique and cycles, etc.), and storage time. To define the best practice for the storage and handling of solution samples, GlaxoSmithKline has undertaken stability experiments over more than a decade, initially to support the implementation of new automated liquid stores (ALS) and, subsequently, to enhance storage and use of compounds in solution through an understanding of compound degradation under storage and assay conditions. The experiments described used a number of technologies, including hyphenated liquid chromatography, electrospray mass spectrometry, flow chemiluminescence nitrogen detection, nuclear magnetic resonance, and Karl Fischer titration.

    Publication / Type:
    Journal of Biomolecular Screening 2009:547-556
    Related Subject:
    GSK
    Link:
    http://jbx.sagepub.com/content/14/5/547.abstract
  • Long-Term Storage of Compound Solutions for High-Throughput Screening by Using a Novel 1536-Well Microplate Pfeifer M J, Scheel G

    Institution: Novartis

    Publication: J Biomol Screen June 2009 vol. 14 no. 5 492-498

    2009 abstract

    This report describes the features and the performance of a new and significantly improved 1536-well microplate design. The design allows for simple, automation-friendly, and cost-effective storage of compound solutions for high-throughput screening. The plate design is based on Society for Biomolecular Sciences standards for microplates and can be molded from polystyrene or cycloolefin copolymer, thus making the plate suitable for use with acoustic dispensing as well as other conventional liquid dispensing in the nanoliter range. For a 9:1 DMSO/water mix as solvent, the novel plate design has shown to perform over 4 months with only minor losses in solvent. Thus, this novel plate design creates the basis for further reductions in compound storage volumes and allows for an increase in the storage times for microliter volumes for up to a year or more. The high protection against solvent evaporation is also visible for aqueous solutions, thus allowing for reduced edge effects during screening campaigns.

    Publication / Type:
    J Biomol Screen June 2009 vol. 14 no. 5 492-498
    Related Subject:
    Long-Term Storage 1536-Well Microplate
    Link:
    http://jbx.sagepub.com/content/14/5/492.abstract
  • Applications of the Charged Aerosol Detector in Compound Management Sinclair I, Charles I

    Institution: AstraZeneca

    Publication: J Biomol Screen June 2009 vol. 14 no. 5 531-537

    2009 abstract

    Recent literature has described the exciting development of a new universal detection technology for high-performance liquid chromatography (HPLC), as well as some exploratory work on its application to quantitative measurement of solutes at millimolar concentrations. The new methodology, known as charged aerosol detection (CAD), has been recognized as a viable alternative to evaporative light-scattering detection and refractive index detection that, like CAD, respond to molecular structures independently of their absorbance, or lack thereof, in the ultraviolet region of the electromagnetic spectrum. In this article, the authors exemplify their use of CAD in-line with HPLC and mass spectrometry (MS) to provide both stand-alone and complementary information that aids decision making for sample storage and processing practices in the compound management setting. Illustrations include monitoring contaminants leached from different plate materials into the solvent dimethyl sulphoxide (DMSO) and profiling the concentrations of solutions destined for liquid storage and dispensing to assays, with the aim of improving processes.

    Publication / Type:
    J Biomol Screen June 2009 vol. 14 no. 5 531-537
    Related Subject:
    Charged Aerosol Detector Compound
    Link:
    http://jbx.sagepub.com/content/14/5/531.abstract
  • Best Practices in Compound Management for Preserving Compound Integrity and Accurately Providing Samples for Assays Matson S L, Chatterjee M, Stock D A, Leet J E, Dumas E A, Ferrante C D, Monahan W E, Cook L S, Watso

    Institution: Bristol-Myers Squibb Company

    Publication: Journal of Biomolecular Screening 2009:476-484

    2009 abstract

    Preserving the integrity of the compound collection and providing high-quality materials for drug discovery in an efficient and cost-effective manner are 2 major challenges faced by compound management (CM) at Bristol-Myers Squibb (BMS). The demands on CM include delivering hundreds of thousands of compounds a year to a variety of operations. These operations range from single-compound requests to hit identification support and just-in-time assay plate provision for lead optimization. Support needs for these processes consist of the ability to rapidly provide compounds as solids or solutions in a variety of formats, establishing proper long- and short-term storage conditions and creating appropriate methods for handling concentrated, potent compounds for delivery to sensitive biological assays. A series of experiments evaluating the effects of processing compounds with volatile solvents, storage conditions that can induce freeze/thaw cycles, and the delivery of compounds were performed. This article presents the results of these experiments and how they affect compound integrity and the accuracy of compound management processes.

    Publication / Type:
    Journal of Biomolecular Screening 2009:476-484
    Related Subject:
    Preserving Integrity Accurately Assays
    Link:
    http://jbx.sagepub.com/content/14/5/476.abstract
  • High-Quality Cost-Effective Compound Management Support for HTS Zaragoza-Sundqvist M, Eriksson H, Rohman M, Greasley PJ

    Institution: AstraZeneca

    Publication: Journal of Biomolecular Screening 2009:509-514

    2009 abstract

    Four years ago, the first acoustic droplet ejectors (ADEs) were launched on the market, providing a new generation of high-throughput noncontact liquid handlers that outclassed traditional contact instruments in almost every respect. This introduction of noncontact dispensing has triggered radical changes to the screening/compound management interface. Higher quality is achieved through greater accuracy and precision, whereas lower sample volumes can be used, and 1536 plate formats have become a reliable reality. Prior to the ADE instrument launch, 1536 assay-ready plate preparation was a high-effort enterprise requiring users to spend time developing liquid-handling methods along with daily fine-tuning of instruments to reach the desired level of performance. By overcoming the nanoliter dispensing hurdle and successfully transferring assays to high-density formats, a new dimension for cutting costs has emerged. Once the screening customer has adapted to this new world, the rules of supply can also change, with the traditional automated plate store no longer being necessary when the compound library can be stored in 1536 plates. Processing efficiency recently has been further supported by innovative new automation-friendly solutions such as plate desealers, prolonging the life span of working plate copies. Both cost and waste control have never had a higher profile, and noncontact dispensing contributes to these important areas. In some processes (e.g., when piercing septa), contact dispensing remains the best option, but cost control is still essential, and an innovative solution to minimize DMSO consumption from tip washing has had a big impact on consumable budget without compromising quality.

    Publication / Type:
    Journal of Biomolecular Screening 2009:509-514
    Related Subject:
    High-Quality Cost-Effective HTS
    Link:
    http://jbx.sagepub.com/content/14/5/509.abstract
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