7b45: Difference between revisions
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==Notum complex with ARUK3003934== | ==Notum complex with ARUK3003934== | ||
<StructureSection load='7b45' size='340' side='right'caption='[[7b45]]' scene=''> | <StructureSection load='7b45' size='340' side='right'caption='[[7b45]], [[Resolution|resolution]] 1.38Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7B45 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B45 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7b45]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7B45 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B45 FirstGlance]. <br> | ||
</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=7b45 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b45 OCA], [https://pdbe.org/7b45 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b45 RCSB], [https://www.ebi.ac.uk/pdbsum/7b45 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b45 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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>, <scene name='pdbligand=SWQ:6-(3-methylsulfanylphenyl)sulfanyl-2~{H}-[1,2,4]triazolo[4,3-b]pyridazin-3-one'>SWQ</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/[Wnt_protein]_O-palmitoleoyl-L-serine_hydrolase [Wnt protein] O-palmitoleoyl-L-serine hydrolase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.98 3.1.1.98] </span></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=7b45 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b45 OCA], [https://pdbe.org/7b45 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b45 RCSB], [https://www.ebi.ac.uk/pdbsum/7b45 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b45 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/NOTUM_HUMAN NOTUM_HUMAN]] May deacetylate GlcNAc residues on cell surface glycans. | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:34939789</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7b45" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Fish P]] | [[Category: Fish, P]] | ||
[[Category: Jones | [[Category: Jones, E Y]] | ||
[[Category: Hydrolase]] | |||
[[Category: Notum inhibitor]] | |||
Revision as of 21:09, 27 July 2022
Notum complex with ARUK3003934Notum complex with ARUK3003934
Structural highlights
Function[NOTUM_HUMAN] May deacetylate GlcNAc residues on cell surface glycans. Publication Abstract from PubMedNotum 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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