High-Throughput Screening: Searching for Higher Productivity

Fox, Sandra; Farr-Jones, Shauna; Sopchak, Lynne; Boggs, Amy F; Comley, J. C. W.

doi:10.1177/1087057104265290

Cited by 53 publications

(26 citation statements)

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“…When combinatorial chemistry first appeared on the pharmaceutical scene the emphasis was on the production of chemical arrays (or libraries) containing large numbers of compounds, either as singletons or in mixtures [1][2][3]. Its development, in conjunction with a number of key automation improvements such as high throughput screening (HTS), meant that hundreds of thousands of compounds could be routinely tested for biological activity [4,5].…”

Section: Introductionmentioning

confidence: 99%

How Large Does a Compound Screening Collection Need To Be?

Lipkin¹,

Stevens²,

Livingstone³

et al. 2008

CCHTS

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Increasingly, chemical libraries are being produced which are focused on a biological target or group of related targets, rather than simply being constructed in a combinatorial fashion. A screening collection compiled from such libraries will contain multiple analogues of a number of discrete series of compounds. The question arises as to how many analogues are necessary to represent each series in order to ensure that an active series will be identified. Based on a simple probabilistic argument and supported by in-house screening data, guidelines are given for the number of compounds necessary to achieve a "hit", or series of hits, at various levels of certainty. Obtaining more than one hit from the same series is useful since this gives early acquisition of SAR (structure-activity relationship) and confirms a hit is not a singleton. We show that screening collections composed of only small numbers of analogues of each series are sub-optimal for SAR acquisition. Based on these studies, we recommend a minimum series size of about 200 compounds. This gives a high probability of confirmatory SAR (i.e. at least two hits from the same series). More substantial early SAR (at least 5 hits from the same series) can be gained by using series of about 650 compounds each. With this level of information being generated, more accurate assessment of the likely success of the series in hit-to-lead and later stage development becomes possible.

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Section: Introductionmentioning

confidence: 99%

How Large Does a Compound Screening Collection Need To Be?

Lipkin¹,

Stevens²,

Livingstone³

et al. 2008

CCHTS

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“…11,12 Typically, hundreds of thousands to millions of compounds are screened at a single concentration using a suitable assay. Compounds which cause a statistically significant effect are retested at a single or multiple concentrations to confirm activity and determine potency.…”

Section: Resultsmentioning

confidence: 99%

Identification and Characterization of Acidic Mammalian Chitinase Inhibitors

et al. 2010

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Acidic mammalian chitinase (AMCase) is a member of the glycosyl hydrolase 18 family (EC 3.2.1.14) that has been implicated in the pathophysiology of allergic airway disease such as asthma. Small molecule inhibitors of AMCase were identified using a combination of high-throughput screening, fragment screening, and virtual screening techniques and characterized by enzyme inhibition and NMR and Biacore binding experiments. X-ray structures of the inhibitors in complex with AMCase revealed that the larger more potent HTS hits, e.g. 5-(4-(2-(4-bromophenoxy)ethyl)piperazine-1-yl)-1H-1,2,4-triazol-3-amine 1, spanned from the active site pocket to a hydrophobic pocket. Smaller fragments identified by FBS occupy both these pockets independently and suggest potential strategies for linking fragments. Compound 1 is a 200 nM AMCase inhibitor which reduced AMCase enzymatic activity in the bronchoalveolar lavage fluid in allergen-challenged mice after oral dosing.

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“…Since the early 1980s, when compound library screening campaigns consisted of ELISA, HPLC and basic binding assays performed in tubes, efforts have been made to improve throughput, accuracy, precision and sensitivity [22,42]. The improvement in throughput and assay techniques is nicely highlighted in a review by Charles Lunn [22].…”

Section: High-throughput Screening and Its Compatibility To Label-frementioning

confidence: 98%

Using label-free screening technology to improve efficiency in drug discovery

Halai

Cooper

2012

Expert Opinion on Drug Discovery

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The limitations associated with the use of transfected cell lines and the use of label-based assays are gradually being realized. As such, greater emphasis is being placed on label-free biophysical techniques using native cell lines. The introduction of 96- and 384-well plate label-free systems is helping to broker a wider acceptance of these approaches in high-throughput screening. However, potential users of the technologies remain skeptical, primarily because the physical basis of the signals generated, and their contextual relevance to cell biology and signal transduction, has not been fully elucidated. Until this is done, these new technology platforms are more likely to complement, rather than replace, traditional screening platforms.

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High-Throughput Screening: Searching for Higher Productivity

Abstract: HighTech Business Decisions is a consulting firm specializing in benchmarking studies, customized market analysis, industry reports, and customer loyalty surveys for companies serving pharmaceutical and biotechnology markets.

Cited by 53 publications

References 0 publications

How Large Does a Compound Screening Collection Need To Be?

How Large Does a Compound Screening Collection Need To Be?

Identification and Characterization of Acidic Mammalian Chitinase Inhibitors

Using label-free screening technology to improve efficiency in drug discovery

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