View source for 8xgv


==Optimization Efforts for Identification of Novel Highly Potent Keap1-Nrf2 Protein-Protein Interaction (PPI) Inhibitors==
<StructureSection load='8xgv' size='340' side='right'caption='[[8xgv]], [[Resolution|resolution]] 1.42&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8xgv]] 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=8XGV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8XGV 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]] 1.42&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1LVC:(2~{R},3~{S})-3-[[(2~{S})-2-[4-[(3-ethoxypyridin-2-yl)methyl]phenyl]-2-fluoranyl-ethanoyl]amino]-2-methyl-3-(4-methylphenyl)propanoic+acid'>A1LVC</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</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=8xgv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8xgv OCA], [https://pdbe.org/8xgv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8xgv RCSB], [https://www.ebi.ac.uk/pdbsum/8xgv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8xgv ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KEAP1_HUMAN KEAP1_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
In research focused on protein-protein interaction (PPI) inhibitors, the optimization process to achieve both high inhibitory activity and favorable physicochemical properties remains challenging. Our previous study reported the discovery of novel and bioavailable Keap1-Nrf2 PPI inhibitor 8 which exhibited moderate in vivo activity in rats. In this work, we present our subsequent efforts to optimize this compound. Two distinct approaches were employed, targeting high energy water molecules and Ser602 as "hot spots" from the anchor with good aqueous solubility, metabolic stability, and membrane permeability. Through ligand efficiency (LE)-guided exploration, we identified two novel inhibitors 22 and 33 with good pharmacokinetics (PK) profiles and more potent in vivo activities, which appear to be promising chemical probes among the existing inhibitors.

Optimization Efforts for Identification of Novel Highly Potent Keap1-Nrf2 Protein-Protein Interaction Inhibitors.,Otake K, Hara Y, Ubukata M, Inoue M, Nagahashi N, Motoda D, Ogawa N, Hantani Y, Hantani R, Adachi T, Nomura A, Yamaguchi K, Maekawa M, Mamada H, Motomura T, Sato M, Harada K J Med Chem. 2024 Mar 14;67(5):3741-3763. doi: 10.1021/acs.jmedchem.3c02171. Epub , 2024 Feb 26. PMID:38408347<ref>PMID:38408347</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8xgv" 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: Hara Y]]
[[Category: Harada K]]
[[Category: Inoue M]]
[[Category: Maekawa M]]
[[Category: Mamada H]]
[[Category: Motoda D]]
[[Category: Motomura T]]
[[Category: Nagahashi N]]
[[Category: Nomura A]]
[[Category: Ogawa N]]
[[Category: Otake K]]
[[Category: Sato M]]
[[Category: Ubukata M]]
[[Category: Yamaguchi K]]