5lwt | pdb_00005lwt

Endothiapepsin in complex with a methoxylated derivative of fragment 177

spinqualitylabelsall models 5lwt, resolution 1.07Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5lwt is a 1 chain structure with sequence from Cryphonectria parasitica. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.069Å Ligands: 7B3, ACT, DMS, GOL, TFA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CARP_CRYPA Publication Abstract from PubMed 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. 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 EE, Ehrmann FR, Radeva N, Zitzer N, Linne U, Linser R, Heine A, Klebe G Angew Chem Int Ed Engl. 2017 Feb 6;56(7):1908-1913. doi: 10.1002/anie.201609824. , Epub 2017 Jan 18. PMID:28097765 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Pepsin

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