NanoStore: A Concept for Logistical Improvements of Compound Handling in High-Throughput Screening

Benson, Neil; Boyd, Helen; Everett, Jeremy R.; Fries, Joachim; Gribbon, Philip; Haque, Nuzrul; Henco, Karsten; Jessen, Timm; Martin, William H.; Mathewson, Travis; Sharp, Robert E.; Spencer, Robin W.; Stühmeier, Frank; Wallace, Mark; Winkler, Dirk

doi:10.1177/1087057105277234

Cited by 18 publications

(8 citation statements)

References 17 publications

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“…A key element of Evotec's fragment compound handling for high concentration bioassays is the application of the NanoStore concept that was co-developed by Pfizer and Evotec scientists [26]. The original purpose of NanoStore was to logistically uncouple the compound handling from the wet screening process in HTS.…”

Section: Evoscreen™ Detection Technologymentioning

confidence: 99%

Fragment Based Drug Discovery Using Fluorescence Correlation Spectroscopy Techniques: Challenges and Solutions

Hesterkamp

Barker²,

Davenport³

et al. 2007

CTMC

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Novel starting points for medicinal chemistry programmes can be effectively identified by screening libraries of fragment molecules in biochemical assays at high concentration. The key to success with this approach is the combination of a high quality fragment library with sensitive biochemical screening methods. There are an increasing number of literature reports where weakly active fragment molecules have been identified by high concentration biochemical assays. We have successfully demonstrated the use of high concentration screening of fragments, using a portfolio of single-molecule Fluorescence Correlation Spectroscopy (FCS+plus) detection techniques to ensure the highest reproducibility and sensitivity, and have determined the binding mode of active fragments to target proteins by X-ray crystallography. Further biophysical detection methods are reviewed for their applicability to studies of fragment binding.

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Section: Evoscreen™ Detection Technologymentioning

confidence: 99%

Fragment Based Drug Discovery Using Fluorescence Correlation Spectroscopy Techniques: Challenges and Solutions

Hesterkamp

Barker²,

Davenport³

et al. 2007

CTMC

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“…To explore the performance of a novel compound dry-down procedure, 4 we carried out a concordance experiment using neutral endopeptidase as a test system. The relative output from screening a file subset was used as a measure of success.…”

Section: Resultsmentioning

confidence: 99%

“…Subsequent experiments were consistent with this conclusion. 4 In addition to facilitating this understanding, the model has also allowed for a range of conditions to be readily explored that have led to the design of more efficient experiments for any future work. For example, we have concluded that screens should be used that will meet the dual need for a relatively high number of actives in the screened population (> 0.1%) and that also display activities spanning the range of percent effects of interest (e.g., 40%-100%).…”

Section: Discussionmentioning

confidence: 99%

Improving the Design and Analysis of High-Throughput Screening Technology Comparison Experiments Using Statistical Modeling

et al. 2006

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Contemporary small-molecule drug discovery frequently involves the screening of large compound files as a core activity. Subsequently cost, speed, and safety become critical issues. In order to meet this need, numerous technologies have been developed to allow mix and measure approaches, facilitate miniaturization, and to increase speed and to minimize the use of potentially hazardous reagents such as radioactive materials. However, despite the on-paper advantages of these new technologies, risks can remain undefined. For example, the question of whether the novel method will facilitate identification of active chemical series in a way that is comparable with conventional methods arises. In order to address this question, we have taken the approach of carrying out experiments to directly compare the output of high-throughput screens using a given novel approach and a traditional method. The concordance between the screening methods can then be determined via comparison of the numbers and structures of the active molecules identified. This article describes the approach taken in our laboratory to minimize variability in such experiments and shows data that exemplifies the general result of lower than expected concordance. Statistical modeling was subsequently used to facilitate this interpretation. The model used β-distribution function to generate a real-activity frequency relationship with added normal random error and occasional outliers to represent assay variability. Hence, the effect of assay parameters such as the threshold, the number of real actives, and the number of outliers and the standard deviation could readily be explored. The model was found to describe the data reasonably and moreover was found to be of great utility when it came to planning further optimal experiments. A key conclusion from the model was that concordance between screening methods could appear poor even when one approach is compared with itself. This occurs simply because the result is a function of assay threshold, standard deviation and the true compound % activity. In response to this finding we have adopted alternative experimental designs that more reliably measure the concordance between screening methods. (Journal of Biomolecular Screening 2006:5-12)

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“…GSK has undertaken various experiments to investigate the reconstitution of dried compounds of diverse chemical properties. Initial testing with 2-hydroxypropyl-βcyclodextrin excipient 18,19 with a small number of compounds did not show improved compound resolubilization of dried-down compounds (data not shown). Further experiments will be needed for more conclusive results with various other excipients.…”

Section: Compound Reconstitution Experimentsmentioning

confidence: 96%

Next-Generation Compound Delivery Platforms to Support Miniaturized Biology

et al. 2019

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Recent advancements in science and engineering are revolutionizing our understanding of an individual's disease, and with this knowledge we are gaining an increasingly sophisticated understanding of how discovery can be transformed to deliver personalized medicines. To reach this future state, we must reengineer our approach to enable the use of more relevant human cellular models earlier in the drug discovery process. Stem cells and primary human cells represent more disease-relevant models than immortalized cell lines; however, due to both availability and cost, their use is limited in lead generation activities. Miniaturization of cellular assays below microtiter plate volumes will enable the use of more relevant cells in screening, but this would require a change in how test molecules are introduced to the biology. With these shifting paradigms, Discovery Supply teams at GlaxoSmithKline (GSK) are modernizing our sample handling approaches. Various emerging technologies such as microarrays, nanowells, and microfluidic devices could bring fundamental changes in conventional sample handling support as we transition from microtiter plates to well-less platforms. The discussion here is exploratory in nature and reviews ongoing proof-of-concept experiments. Our ultimate goal is to industrialize the sample management platforms to support future miniaturized biological assay systems.

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NanoStore: A Concept for Logistical Improvements of Compound Handling in High-Throughput Screening

Cited by 18 publications

References 17 publications

Fragment Based Drug Discovery Using Fluorescence Correlation Spectroscopy Techniques: Challenges and Solutions

Fragment Based Drug Discovery Using Fluorescence Correlation Spectroscopy Techniques: Challenges and Solutions

Improving the Design and Analysis of High-Throughput Screening Technology Comparison Experiments Using Statistical Modeling

Next-Generation Compound Delivery Platforms to Support Miniaturized Biology

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