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7lrl

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'''Unreleased structure'''
 
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The entry 7lrl is ON HOLD until Paper Publication
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==Co-complex CYP46A1 with 7742 (Soticlestat/TAK-935))==
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<StructureSection load='7lrl' size='340' side='right'caption='[[7lrl]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[7lrl]] 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=7LRL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LRL FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.995&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=YBS:[4-oxidanyl-4-(phenylmethyl)piperidin-1-yl]-(2-pyridin-4-ylpyridin-3-yl)methanone'>YBS</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lrl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lrl OCA], [https://pdbe.org/7lrl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lrl RCSB], [https://www.ebi.ac.uk/pdbsum/7lrl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lrl ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/CP46A_HUMAN CP46A_HUMAN] Involved in the turnover of cholesterol. It converts cholesterol into 24S-hydroxycholesterol and, to a lesser extent, 25-hydroxycholesterol.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Cholesterol 24-hydroxylase (CH24H, CYP46A1), a brain-specific cytochrome P450 (CYP) family enzyme, plays a role in the homeostasis of brain cholesterol by converting cholesterol to 24S-hydroxycholesterol (24HC). Despite a wide range of potential of CH24H as a drug target, no potent and selective inhibitors have been identified. Here, we report on the structure-based drug design (SBDD) of novel 4-arylpyridine derivatives based on the X-ray co-crystal structure of hit derivative 1b. Optimization of 4-arylpyridine derivatives led us to identify 3v ((4-benzyl-4-hydroxypiperidin-1-yl)(2,4'-bipyridin-3-yl)methanone, IC50 = 7.4 nM) as a highly potent, selective, and brain-penetrant CH24H inhibitor. Following oral administration to mice, 3v resulted in a dose-dependent reduction of 24HC levels in the brain (1, 3, and 10 mg/kg). Compound 3v (soticlestat, also known as TAK-935) is currently under clinical investigation for the treatment of Dravet syndrome and Lennox-Gastaut syndrome as a novel drug class for epilepsies.
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Authors: Lane, W., Yano, J.
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Discovery of Soticlestat, a Potent and Selective Inhibitor for Cholesterol 24-Hydroxylase (CH24H).,Koike T, Yoshikawa M, Ando HK, Farnaby W, Nishi T, Watanabe E, Yano J, Miyamoto M, Kondo S, Ishii T, Kuroita T J Med Chem. 2021 Aug 13. doi: 10.1021/acs.jmedchem.1c00864. PMID:34387987<ref>PMID:34387987</ref>
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Description: Co-complex CYP46A1 with 7742 (Soticlestat/TAK-935))
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Lane, W]]
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<div class="pdbe-citations 7lrl" style="background-color:#fffaf0;"></div>
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[[Category: Yano, J]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Lane W]]
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[[Category: Yano J]]

Current revision

Co-complex CYP46A1 with 7742 (Soticlestat/TAK-935))

PDB ID 7lrl

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