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Drug Discovery at t...
Drug Discovery at the Single Molecule Level: Inhibition-in-Solution Assay of Membrane-Reconstituted beta-Secretase Using Single-Molecule Imaging
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- Gunnarsson, Anders, 1981 (author)
- AstraZeneca AB
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- Snijder, Arjan, 1971 (author)
- AstraZeneca AB
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- Hicks, J. (author)
- AstraZeneca AB
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- Gunnarsson, J. (author)
- AstraZeneca AB
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- Höök, Fredrik, 1966 (author)
- Chalmers tekniska högskola,Chalmers University of Technology
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- Geschwindner, S. (author)
- AstraZeneca AB
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(creator_code:org_t)
- 2015-04-10
- 2015
- English.
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In: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 87:8, s. 4100-4103
- Related links:
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http://dx.doi.org/10...
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https://research.cha...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Inhibition-in-solution assays (ISA) employing surface-based biosensors such as surface plasmon resonance (SPR) are an effective screening approach in drug discovery. However, analysis of potent binders remains a significant hurdle due to limited sensitivity and accompanied depletion of the inhibiting compounds due to high protein concentrations needed for detectable binding signals. To overcome this limitation, we explored a microscopy-based single-molecule ISA compatible with liposome-reconstituted membrane proteins. Using a set of validated small molecule inhibitors against beta-secretase 1 (BACE1), the assay was benchmarked with respect to sensitivity and dynamic range against SPR. We demonstrate that the dynamic range of measurable affinities is greatly extended by more than 2 orders of magnitude as compared to SPR, thus facilitating measurements of highly potent (K-d
Subject headings
- NATURVETENSKAP -- Kemi -- Analytisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Analytical Chemistry (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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