View source for 8ivg


==Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1/Nrf2 PPI Inhibitor for Treatment of Chronic Kidney Disease==
<StructureSection load='8ivg' size='340' side='right'caption='[[8ivg]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8ivg]] is a 1 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=8IVG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8IVG 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=SGO:(3S)-3-(4-methylphenyl)-3-[2-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanoylamino]propanoic+acid'>SGO</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=8ivg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ivg OCA], [https://pdbe.org/8ivg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ivg RCSB], [https://www.ebi.ac.uk/pdbsum/8ivg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ivg ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KEAP1_HUMAN KEAP1_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Oxidative stress is one of the causes of progression of chronic kidney disease (CKD). Activation of the antioxidant protein regulator Nrf2 by inhibition of the Keap1-Nrf2 protein-protein interaction (PPI) is of interest as a potential treatment for CKD. We report the identification of the novel and weak PPI inhibitor 7 with good physical properties by a high throughput screening (HTS) campaign, followed by structural and computational analysis. The installation of only methyl and fluorine groups successfully provided the lead compound 25, which showed more than 400-fold stronger activity. Furthermore, these dramatic substituent effects can be explained by the analysis of using isothermal titration calorimetry (ITC). Thus, the resulting 25, which exhibited high oral absorption and durability, would be a CKD therapeutic agent because of the dose-dependent manner for up-regulation of the antioxidant protein heme oxigenase-1 (HO-1) in rat kidneys.

Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1-Nrf2 PPI Inhibitor.,Otake K, Ubukata M, Nagahashi N, Ogawa N, Hantani Y, Hantani R, Adachi T, Nomura A, Yamaguchi K, Maekawa M, Mamada H, Motomura T, Sato M, Harada K ACS Med Chem Lett. 2023 Apr 7;14(5):658-665. doi: 10.1021/acsmedchemlett.3c00067. , eCollection 2023 May 11. PMID:37197451<ref>PMID:37197451</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8ivg" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Adachi T]]
[[Category: Hantani R]]
[[Category: Hantani Y]]
[[Category: Harada K]]
[[Category: Maekawa M]]
[[Category: Mamada H]]
[[Category: Motomura T]]
[[Category: Nagahashi N]]
[[Category: Nomura A]]
[[Category: Ogawa N]]
[[Category: Otake K]]
[[Category: Sato M]]
[[Category: Ubukata M]]
[[Category: Yamaguchi K]]