6zuv: Difference between revisions
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==Notum fragment 286== | |||
<StructureSection load='6zuv' size='340' side='right'caption='[[6zuv]], [[Resolution|resolution]] 1.54Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZUV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZUV FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.54Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B1J:[1-(4-chlorophenyl)-1,2,3-triazol-4-yl]methanol'>B1J</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6zuv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zuv OCA], [https://pdbe.org/6zuv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zuv RCSB], [https://www.ebi.ac.uk/pdbsum/6zuv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zuv ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-triazole 7 as an attractive starting point for a structure-based drug design hit-to-lead program. Optimization of 7 identified oxadiazol-2-one 23dd as a preferred example with properties consistent with drug-like chemical space. Screening 23dd in a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of 23dd demonstrated good plasma exposure and partial blood-brain barrier penetration. Significant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling. | |||
5-Phenyl-1,3,4-oxadiazol-2(3H)-ones Are Potent Inhibitors of Notum Carboxylesterase Activity Identified by the Optimization of a Crystallographic Fragment Screening Hit.,Mahy W, Willis NJ, Zhao Y, Woodward HL, Svensson F, Sipthorp J, Vecchia L, Ruza RR, Hillier J, Kjaer S, Frew S, Monaghan A, Bictash M, Salinas PC, Whiting P, Vincent JP, Jones EY, Fish PV J Med Chem. 2020 Oct 30. doi: 10.1021/acs.jmedchem.0c01391. PMID:33124429<ref>PMID:33124429</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6zuv" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
==See Also== | |||
*[[Carboxylesterase 3D structures|Carboxylesterase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Jones EY]] | |||
[[Category: Zhao Y]] | |||
