7k41: Difference between revisions
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==Bacterial O-GlcNAcase (OGA) with compound== | |||
<StructureSection load='7k41' size='340' side='right'caption='[[7k41]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7k41]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7K41 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7K41 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=VUA:4-(4-methylpiperidin-1-yl)-N-(2-phenylethyl)pyrimidin-2-amine'>VUA</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein_O-GlcNAcase Protein O-GlcNAcase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.169 3.2.1.169] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7k41 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k41 OCA], [http://pdbe.org/7k41 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7k41 RCSB], [http://www.ebi.ac.uk/pdbsum/7k41 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7k41 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/OGA_BACTN OGA_BACTN]] Biological function unknown. Capable of hydrolyzing the glycosidic link of O-GlcNAcylated proteins. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
O-GlcNAcase (OGA) has received increasing attention as an attractive therapeutic target for tau-mediated neurodegenerative disorders; however, its role in these pathologies remains unclear. Therefore, potent chemical tools with favorable pharmacokinetic profiles are desirable to characterize this enzyme. Herein, we report the discovery of a potent and novel OGA inhibitor, compound 5i, comprising an aminopyrimidine scaffold, identified by virtual screening based on multiple methodologies combining structure-based and ligand-based approaches, followed by sequential optimization with a focus on ligand lipophilicity efficiency. This compound was observed to increase the level of O-GlcNAcylated protein in cells and display suitable pharmacokinetic properties and brain permeability. Crystallographic analysis revealed that the chemical series bind to OGA via characteristic hydrophobic interactions, which resulted in a high affinity for OGA with moderate lipophilicity. Compound 5i could serve as a useful chemical probe to help establish a proof-of-concept of OGA inhibition as a therapeutic target for the treatment of tauopathies. | |||
Discovery of a Novel and Brain-Penetrant O-GlcNAcase Inhibitor via Virtual Screening, Structure-Based Analysis, and Rational Lead Optimization.,Tawada M, Fushimi M, Masuda K, Sun H, Uchiyama N, Kosugi Y, Lane W, Tjhen R, Endo S, Koike T J Med Chem. 2021 Jan 6. doi: 10.1021/acs.jmedchem.0c01712. PMID:33404239<ref>PMID:33404239</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7k41" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Ecoli]] | |||
[[Category: Large Structures]] | |||
[[Category: Protein O-GlcNAcase]] | |||
[[Category: Lane, W]] | |||
[[Category: Sang, B]] | |||
[[Category: Snell, G]] | [[Category: Snell, G]] | ||
[[Category: Tjhen, R]] | [[Category: Tjhen, R]] | ||
[[Category: Oga]] | |||
[[Category: Sbdd]] | |||
[[Category: Structure based drug design]] | |||
[[Category: Transferase]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||
[[Category: Virtual screening]] | |||
