7b50 | pdb_00007b50

Notum complex with ARUK3003778

spinqualitylabelsall models 7b50, resolution 1.33Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7b50 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.33Å Ligands: DMS, SO4, SXQ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NOTUM_HUMAN May deacetylate GlcNAc residues on cell surface glycans. Publication Abstract from PubMed Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC50 < 500 nM. A critical selection process was then applied with two clusters and two singletons (1-4d) selected for hit validation. Optimization of 4d guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/beta-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-b]pyradizin-3(2H)-one series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. These results demonstrate the value of VS with well-designed docking models based on X-ray structures. Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity.,Steadman D, Atkinson BN, Zhao Y, Willis NJ, Frew S, Monaghan A, Patel C, Armstrong E, Costelloe K, Magno L, Bictash M, Jones EY, Fish PV, Svensson F J Med Chem. 2022 Jan 13;65(1):562-578. doi: 10.1021/acs.jmedchem.1c01735. Epub, 2021 Dec 23. PMID:34939789 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Carboxylesterase 3D structures

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