View source for 8qpn


==LTA4 hydrolase in complex with compound 6(S)==
<StructureSection load='8qpn' size='340' side='right'caption='[[8qpn]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8qpn]] 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=8QPN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8QPN 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&#8491;</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=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=WSL:(2S)-2-azanyl-3-[5-[4-(5-chloranyl-3-fluoranyl-pyridin-2-yl)oxyphenyl]-1,2,3,4-tetrazol-2-yl]propan-1-ol'>WSL</scene>, <scene name='pdbligand=YB:YTTERBIUM+(III)+ION'>YB</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=8qpn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8qpn OCA], [https://pdbe.org/8qpn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8qpn RCSB], [https://www.ebi.ac.uk/pdbsum/8qpn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8qpn ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/LKHA4_HUMAN LKHA4_HUMAN] Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity.<ref>PMID:1897988</ref> <ref>PMID:1975494</ref> <ref>PMID:2244921</ref> <ref>PMID:12207002</ref> <ref>PMID:11917124</ref> <ref>PMID:15078870</ref> <ref>PMID:18804029</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The discovery of chiral amino alcohols derived from our previously disclosed clinical LTA4H inhibitor LYS006 is described. In a biochemical assay, their optical antipodes showed similar potencies, which could be rationalized by the cocrystal structures of these compounds bound to LTA4H. Despite comparable stabilities in liver microsomes, they showed distinct in vivo PK properties. Selective O-phosphorylation of the (R)-enantiomers in blood led to clearance values above the hepatic blood flow, whereas the (S)-enantiomers were unaffected and exhibited satisfactory metabolic stabilities in vivo. Introduction of two pyrazole rings led to compound (S)-2 with a more balanced distribution of polarity across the molecule, exhibiting high selectivity and excellent potency in vitro and in vivo. Furthermore, compound (S)-2 showed favorable profiles in 16-week IND-enabling toxicology studies in dogs and rats. Based on allometric scaling and potency in whole blood, compound (S)-2 has the potential for a low oral efficacious dose administered once daily.

Discovery of Amino Alcohols as Highly Potent, Selective, and Orally Efficacious Inhibitors of Leukotriene A4 Hydrolase.,Thoma G, Markert C, Lueoend R, Miltz W, Spanka C, Bollbuck B, Wolf RM, Srinivas H, Penno CA, Kiffe M, Gajewska M, Bednarczyk D, Wieczorek G, Evans A, Beerli C, Rohn TA J Med Chem. 2023 Nov 28. doi: 10.1021/acs.jmedchem.3c01866. PMID:38015154<ref>PMID:38015154</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8qpn" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Srinivas H]]