Purifying the Masses:  Integrating Prepurification Quality Control, High-Throughput LC/MS Purification, and Compound Plating To Feed High-Throughput Screening

Isbell, John; Zhou, Yingyao; Guintu, Christina; Rynd, Matthew; Jiang, Shumei; Petrov, D. M.; Micklash, Ken; Mainquist, Jim; Ek, Jared; Chang, Jim; Weselak, Mark; Backes, Bradley J.; Brailsford, and Andrew; Shave, Darcy

doi:10.1021/cc049892f

Cited by 19 publications

(14 citation statements)

References 30 publications

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“…This summary provides a graphical interface that provides not only confirmation of expected m/z but also UV and ELSD purity. 5,6 Thus, for small, focused libraries of up to 1408 compounds, chemists can get a complete view of the quality of all the compounds synthesized.…”

Section: Resultsmentioning

confidence: 99%

Cherry-Picking in an Orchard: Unattended LC/MS Analysis from an Autosampler with >32,000 Samples Online

Ari

Westling²,

Isbell

2006

SLAS Discovery

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The 1536-well microplate format has widely supplanted the 384-well microplate format for high-throughput screening and for IC 50 assays. Previously, liquid chromatography/mass spectrometry (LC/MS) analyses of such samples required manual transfers of the wells of interest from a 1536-well plate into a 384-well plate. Because this manual transfer introduced a source of potential error, it became clear that a more appropriate solution would be to sample directly from the 1536-well plates. Currently, commercially available 1536-well plate autosamplers are not compatible with Waters LC/MS systems. The authors have modified their CTC PAL autosampler to support injection from up to twenty-four 1536-well plates. This allows them to cherry-pick any sample from up to 36,864 wells on the autosampler. Because of its success at this Institute, sampling from 1536-well plates has not only become the preferred method for LC/MS analysis from IC 50 plates but also become the standard format used for the handling of and the sampling from large combinatorial libraries. (Journal of Biomolecular Screening 2006:318-322)

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Section: Resultsmentioning

confidence: 99%

Cherry-Picking in an Orchard: Unattended LC/MS Analysis from an Autosampler with >32,000 Samples Online

Ari

Westling²,

Isbell

2006

SLAS Discovery

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“…the legacy libraries from this period proved to be multimillion dollar problems as hundreds of thousands of samples had to be purified, reweighed, or simply discarded. 70,[79][80][81] but this cost more than outweighed the cost of screening bad samples, which has been estimated to be as high as $4 million over 5 years for every 10% of the samples that are bad. 111 the good news is that this has left the industry with better libraries and, more important, a dedication to sample quality.…”

Section: Chemical Errormentioning

confidence: 99%

Advances in Improving the Quality and Flexibility of Compound Management

Janzen¹,

Popa‐Burke²

2009

SLAS Discovery

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The process of drug discovery has evolved considerably since the advent of high-throughput screening (HTS) in the 1980s. Experts and opinion leaders today are agreeing that the current trend in the field is a focus on increasing overall quality (target, screening, and compounds), use of multiple screening approaches for lead discovery, and more flexibility in the process. The associated need for increased flexibility and quality control to support existing HTS paradigms as well as lower throughput approaches such as fragment screening, computational chemistry, focused library building, and centralized lead optimization support has required an evolution in compound management (CM, aka sample management or library management). Although there is much less published peer-reviewed data in CM, due to its historical links to HTS, it has followed very similar trends. In recent years, the focus in CM has been increasingly in compound quality and increased flexibility of the process, as opposed to number of compounds dispensed and speed of dispensing, which were standard metrics and indicators used not so long ago. Ideally, to screen the highest quality sample for every assay, one would start with a correct identity and pure solid, make a correct concentration solution in water or water-soluble/assay-compatible solvent that would allow 100% solubilization, and screen it immediately in a biological assay. Neither CM nor screening has advanced sufficiently to deliver this ideal scenario, but many significant advancements have been made in recent years both in terms of quality of compounds in stores and flexibility of the process, which will be reviewed herein.

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“…The amount of PGA produced by fermentation has increased considerably during the last decade. As the purification steps directly correlate with both the yield and the operating costs, a simple and efficient method for protein purification is deserved (Abhinav et al, 2000;Ahuja, 2000;Isbell et al, 2005;Kim et al, 2005;Patrik et al, 2005;Tugcu et al, 2001). In addition, method improvement for accelerating protein purification process has become the focus of interest (Doyle et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Penicillin G acylase purification with the aid of high-throughput screening approach

Jin

Wang

Chu

et al. 2008

Journal of the Chinese Institute of Chemical Engineers

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Purifying the Masses: Integrating Prepurification Quality Control, High-Throughput LC/MS Purification, and Compound Plating To Feed High-Throughput Screening

Cited by 19 publications

References 30 publications

Cherry-Picking in an Orchard: Unattended LC/MS Analysis from an Autosampler with >32,000 Samples Online

Cherry-Picking in an Orchard: Unattended LC/MS Analysis from an Autosampler with >32,000 Samples Online

Advances in Improving the Quality and Flexibility of Compound Management

Penicillin G acylase purification with the aid of high-throughput screening approach

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