7ls4: Difference between revisions

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==Co-complex CYP46A1 with 9129 (1b)==

== Structural highlights ==

<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LS4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LS4 FirstGlance]. <br>

</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=7ls4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ls4 OCA], [https://pdbe.org/7ls4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ls4 RCSB], [https://www.ebi.ac.uk/pdbsum/7ls4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ls4 ProSAT]</span></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]] 2.05Å</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=YCG:[5,5-dimethyl-3-(2-methylphenyl)-4~{H}-pyrazol-1-yl]-pyridin-4-yl-methanone'>YCG</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=7ls4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ls4 OCA], [https://pdbe.org/7ls4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ls4 RCSB], [https://www.ebi.ac.uk/pdbsum/7ls4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ls4 ProSAT]</span></td></tr>

</table>

== 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<ref>PMID:34387987</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

</div>

== References ==

__TOC__

</StructureSection>

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@@ Line 1: / Line 1: @@
 ==Co-complex CYP46A1 with 9129 (1b)==
-<StructureSection load='7ls4' size='340' side='right'caption='[[7ls4]]' scene=''>
+<StructureSection load='7ls4' size='340' side='right'caption='[[7ls4]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LS4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LS4 FirstGlance]. <br>
-</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=7ls4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ls4 OCA], [https://pdbe.org/7ls4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ls4 RCSB], [https://www.ebi.ac.uk/pdbsum/7ls4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ls4 ProSAT]</span></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]] 2.05&#8491;</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=YCG:[5,5-dimethyl-3-(2-methylphenyl)-4~{H}-pyrazol-1-yl]-pyridin-4-yl-methanone'>YCG</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=7ls4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ls4 OCA], [https://pdbe.org/7ls4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ls4 RCSB], [https://www.ebi.ac.uk/pdbsum/7ls4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ls4 ProSAT]</span></td></tr>
 </table>
+<div style="background-color:#fffaf0;">
+== 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<ref>PMID:34387987</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7ls4" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>