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| | <StructureSection load='7ls3' size='340' side='right'caption='[[7ls3]], [[Resolution|resolution]] 2.15Å' scene=''> | | <StructureSection load='7ls3' size='340' side='right'caption='[[7ls3]], [[Resolution|resolution]] 2.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7ls3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LS3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LS3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7ls3]] 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=7LS3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LS3 FirstGlance]. <br> |
| - | </td></tr><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=YCJ:(5-methyl-2-pyridin-4-yl-phenyl)-[4-oxidanyl-4-(phenylmethyl)piperidin-1-yl]methanone'>YCJ</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7lrl|7lrl]]</div></td></tr>
| + | <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=YCJ:(5-methyl-2-pyridin-4-yl-phenyl)-[4-oxidanyl-4-(phenylmethyl)piperidin-1-yl]methanone'>YCJ</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP46A1, CYP46 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Cholesterol_24-hydroxylase Cholesterol 24-hydroxylase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.25 1.14.14.25] </span></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=7ls3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ls3 OCA], [https://pdbe.org/7ls3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ls3 RCSB], [https://www.ebi.ac.uk/pdbsum/7ls3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ls3 ProSAT]</span></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=7ls3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ls3 OCA], [https://pdbe.org/7ls3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ls3 RCSB], [https://www.ebi.ac.uk/pdbsum/7ls3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ls3 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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.
| + | [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. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cholesterol 24-hydroxylase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lane, W]] | + | [[Category: Lane W]] |
| - | [[Category: Yano, J]] | + | [[Category: Yano J]] |
| - | [[Category: Ch24h]]
| + | |
| - | [[Category: Cyp46a1]]
| + | |
| - | [[Category: Drug discovery]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Sbdd]]
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| Structural highlights
Function
CP46A_HUMAN Involved in the turnover of cholesterol. It converts cholesterol into 24S-hydroxycholesterol and, to a lesser extent, 25-hydroxycholesterol.
Publication Abstract from PubMed
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.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Koike T, Yoshikawa M, Ando HK, Farnaby W, Nishi T, Watanabe E, Yano J, Miyamoto M, Kondo S, Ishii T, Kuroita T. Discovery of Soticlestat, a Potent and Selective Inhibitor for Cholesterol 24-Hydroxylase (CH24H). J Med Chem. 2021 Aug 13. doi: 10.1021/acs.jmedchem.1c00864. PMID:34387987 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c00864
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