View source for 9nnj


==Crystal structure of CYP46A1 with 3-chloro-N-[(3M)-3-(1,3-oxazol-5-yl)phenyl]-N-(propan-2-yl)benzene-1-sulfonamide (compound 2)==
<StructureSection load='9nnj' size='340' side='right'caption='[[9nnj]], [[Resolution|resolution]] 2.29&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9nnj]] 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=9NNJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9NNJ 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]] 2.29&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1BZB:3-chloro-N-[(3M)-3-(1,3-oxazol-5-yl)phenyl]-N-(propan-2-yl)benzene-1-sulfonamide'>A1BZB</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</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=9nnj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9nnj OCA], [https://pdbe.org/9nnj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9nnj RCSB], [https://www.ebi.ac.uk/pdbsum/9nnj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9nnj ProSAT]</span></td></tr>
</table>
== 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.
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== Publication Abstract from PubMed ==
Azole-, pyridine-, and pyrimidine-based cytochrome P450 (CYP) inhibitors strongly bind to CYP enzymes through the coordination between the heme iron of CYP and the sp2-nitrogen atoms of heteroaromatic rings, providing potent pharmacological effects by inhibiting the initiation of the catalytic cycles of target CYP enzymes. Although imidazole-, 1,2,4-triazole-, pyridine-, and pyrimidine-based CYP inhibitors have been widely explored, 1,3-oxazole-based CYP inhibitors have received little attention. In this study, we designed and identified novel 1,3-oxazole-based inhibitors of cholesterol 24- hydroxylase (CH24H; CYP46A1), a brain-specific enzyme involved in cholesterol catabolism, to form 24S-hydroxycholesterol. Detailed insights into the CH24H-ligand interactions were provided by the crystal structures of 1,3-oxazole compounds, including high-throughput screening hit 2 and rationally designed inhibitor 3f. Optimization of 3f led to the identification of 1,3-oxazole derivative 4 l as a potent, selective, and brain-penetrable CH24H inhibitor that significantly reduced 24HC levels in the mouse brain. The design of 1,3-oxazole-based CYP inhibitors holds the potential for the discovery of novel inhibitors with significant potency against a broad spectrum of CYP enzymes.

Design and identification of brain-penetrant, potent, and selective 1,3-oxazole-based cholesterol 24-hydroxylase (CH24H) inhibitors.,Ito Y, Kimura E, Nomura I, Watanabe E, Yano J, Skene R, Miyamoto M, Ishii T, Nishi T, Koike T Bioorg Med Chem. 2025 Apr 5;124:118182. doi: 10.1016/j.bmc.2025.118182. PMID:40215592<ref>PMID:40215592</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9nnj" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Skene RJ]]
[[Category: Yano J]]