A False-Positive Screening Hit in Fragment-Based Lead Discovery: Watch out for the Red Herring

Cramer, Jonathan and Schiebel, Johannes and Wulsdorf, Tobias and Grohe, Kristof and Najbauer, Eszter Eva and Ehrmann, Frederik R. and Radeva, Nedyalka and Zitzer, Nina and Linne, Uwe and Linser, Rasmus and Heine, Andreas and Klebe, Gerhard. (2017) A False-Positive Screening Hit in Fragment-Based Lead Discovery: Watch out for the Red Herring. Angewandte Chemie (International Edition), 56 (7). pp. 1908-1913.

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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.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Cramer, Jonathan
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:16 Apr 2019 15:32
Deposited On:16 Apr 2019 15:32

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