View source for 7lae


==CRYSTAL STRUCTURE OF MYELOPEROXIDASE SUBFORM C (MPO) COMPLEX WITH Compound-4==
<StructureSection load='7lae' size='340' side='right'caption='[[7lae]], [[Resolution|resolution]] 2.97&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7lae]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LAE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LAE 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]] 2.97&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=XRV:7-{[1-(4-fluorophenyl)-1H-pyrazol-4-yl]methyl}-1H-[1,2,3]triazolo[4,5-b]pyridin-5-amine'>XRV</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=7lae FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lae OCA], [https://pdbe.org/7lae PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lae RCSB], [https://www.ebi.ac.uk/pdbsum/7lae PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lae ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Myeloperoxidase (MPO), a critical enzyme in antimicrobial host-defense, has been implicated in chronic inflammatory diseases such as coronary artery disease. The design and evaluation of MPO inhibitors for the treatment of cardiovascular disease are reported herein. Starting with the MPO and triazolopyridine 3 crystal structure, novel inhibitors were designed incorporating a substituted pyrazole, which allowed for substituents to interact with hydrophobic and hydrophilic patches in the active site. SAR exploration of the substituted pyrazoles led to piperidine 17, which inhibited HOCl production from activated neutrophils with an IC(50) value of 2.4 muM and had selectivity against thyroid peroxidase (TPO). Optimization of alkylation chemistry on the pyrazole nitrogen facilitated the preparation of many analogs, including macrocycles designed to bridge two hydrophobic regions of the active site. Multiple macrocyclization strategies were pursued to prepare analogs that optimally bound to the active site, leading to potent macrocyclic MPO inhibitors with TPO selectivity, such as compound 30.

Small molecule and macrocyclic pyrazole derived inhibitors of myeloperoxidase (MPO).,Hu CH, Neissel Valente MW, Halpern OS, Jusuf S, Khan JA, Locke GA, Duke GJ, Liu X, Duclos FJ, Wexler RR, Kick EK, Smallheer JM Bioorg Med Chem Lett. 2021 Jun 15;42:128010. doi: 10.1016/j.bmcl.2021.128010. , Epub 2021 Apr 1. PMID:33811992<ref>PMID:33811992</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7lae" style="background-color:#fffaf0;"></div>

==See Also==
*[[Myeloperoxidase|Myeloperoxidase]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Khan JA]]