7bd2

Notum Fragment 810

spinqualitylabelsall models 7bd2, resolution 1.52Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7bd2 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. Ligands: DMS, NUM, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [NOTUM_HUMAN] May deacetylate GlcNAc residues on cell surface glycans. Publication Abstract from PubMed The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 muM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1-phenyl-1,2,3-triazole 7, and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound 7d with IC50 0.0067 muM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development. Structural Analysis and Development of Notum Fragment Screening Hits.,Zhao Y, Mahy W, Willis NJ, Woodward HL, Steadman D, Bayle ED, Atkinson BN, Sipthorp J, Vecchia L, Ruza RR, Harlos K, Jeganathan F, Constantinou S, Costa A, Kjaer S, Bictash M, Salinas PC, Whiting P, Vincent JP, Fish PV, Jones EY ACS Chem Neurosci. 2022 Jul 6;13(13):2060-2077. doi:, 10.1021/acschemneuro.2c00325. Epub 2022 Jun 22. PMID:35731924 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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