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  A false-positive screening hit in fragment-based lead discovery: Watch out for the red herring.

Cramer, J., Schiebel, J., Wulsdorf, T., Grohe, K., Najbauer, E., Ehrmann, F. R., et al. (2017). A false-positive screening hit in fragment-based lead discovery: Watch out for the red herring. Angewandte Chemie International Edition, 56(7), 1908-1913. doi:10.1002/anie.201609824.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-E842-7 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-E84A-8
Genre: Journal Article

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 Creators:
Cramer, J., Author
Schiebel, J., Author
Wulsdorf, T., Author
Grohe, K.1, Author              
Najbauer, E.2, Author              
Ehrmann, F. R., Author
Radeva, N., Author
Zitzer, N., Author
Linne, U., Author
Linser, R.1, Author              
Heine, A., Author
Klebe, G., Author
Affiliations:
1Research Group of Solid-State NMR-2, MPI for Biophysical Chemistry, Max Planck Society, ou_1950286              
2Department of NMR Based Structural Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_578567              

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 Abstract: With the rising popularity of fragment-based approaches in drug development, more and more attention has to be devoted to the detection of false-positive screening results. In particular, the small size and low affinity of fragments drives screening techniques to their limit. The pursuit of a false-positive hit can cause significant loss of time and resources. Here, we present an instructive and intriguing investigation into the origin of misleading assay results for a fragment that emerged as the most potent binder for the aspartic protease endothiapepsin (EP) across multiple screening assays. This molecule shows its biological effect mainly after conversion into another entity through a reaction cascade that involves major rearrangements of its heterocyclic scaffold. The formed ligand binds EP through an induced-fit mechanism involving remarkable electrostatic interactions. Structural information in the initial screening proved to be crucial for the identification of this false-positive hit.

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Language(s): eng - English
 Dates: 2017-01-182017-02-06
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1002/anie.201609824
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Title: Angewandte Chemie International Edition
Source Genre: Journal
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Pages: - Volume / Issue: 56 (7) Sequence Number: - Start / End Page: 1908 - 1913 Identifier: -