3wz8

Endothiapepsin in complex with Gewald reaction-derived inhibitor (8)

spinqualitylabelsall models 3wz8, resolution 1.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3wz8 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 1.45Å Ligands: DMS, IXV, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CARP_CRYPA Publication Abstract from PubMed Successful lead optimization in structure-based drug discovery depends on the correct deduction and interpretation of the underlying structure-activity relationships (SAR) to facilitate efficient decision-making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)-validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X-ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well-established surrogate for e.g. renin and beta-secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation. Tracing binding modes in hit-to-lead optimization: chameleon-like poses of aspartic protease inhibitors.,Kuhnert M, Koster H, Bartholomaus R, Park AY, Shahim A, Heine A, Steuber H, Klebe G, Diederich WE Angew Chem Int Ed Engl. 2015 Feb 23;54(9):2849-53. doi: 10.1002/anie.201411206., Epub 2015 Jan 28. PMID:25630461 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Pepsin

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