View source for 8wtr


==HUMAN SQUALENE SYNTHASE IN COMPLEX WITH (1S,3R)-3-[2-Chloro-5-(2,2-dimethyl-propyl)-13-(2-methoxy-phenyl)-6,8-dioxo-5,6,7,8,10,11-hexahydro-13H-12-oxa-5,9-diaza-benzocycloundecen-9-yl]-cyclohexanecarboxylic acid==
<StructureSection load='8wtr' size='340' side='right'caption='[[8wtr]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8wtr]] 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=8WTR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8WTR 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=KV3:(1~{S},3~{R})-3-[(10~{S})-13-chloranyl-2-(2,2-dimethylpropyl)-10-(2-methoxyphenyl)-3,5-bis(oxidanylidene)-9-oxa-2,6-diazabicyclo[9.4.0]pentadeca-1(15),11,13-trien-6-yl]cyclohexane-1-carboxylic+acid'>KV3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=8wtr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8wtr OCA], [https://pdbe.org/8wtr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8wtr RCSB], [https://www.ebi.ac.uk/pdbsum/8wtr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8wtr ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/FDFT_HUMAN FDFT_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Squalene synthase is one of the most promising pharmaceutical targets to treat hyperlipidemia. Inhibition of the squalene synthase causes a decrease in the hepatic cholesterol concentration. We have already reported the design and synthesis of highly potent benzhydrol-type squalene inhibitors. Although these templates showed unique and potent cyclic active conformations via intramolecular hydrogen bonds, the in vivo cholesterol-lowering efficacy was insufficient. We attempted to improve their potential as an orally active medicine. In our medicinal chemistry effort, cyclized 11-membered ring templates were acquired. The novel series of compounds exhibited potent squalene synthase inhibitory activity, and one of the derivatives, isomer A-(1S, 3R)-14i, showed plasma lipid-lowering efficacy in hamster and marmoset repeated-dose studies. Our findings provide valuable insights into the design and development of novel and unique 11-membered ring-type highly potent squalene synthase inhibitors.

Discovery of Novel 11-Membered Templates as Squalene Synthase Inhibitors.,Haginoya N, Suzuki M, Suzuki M, Ishigai Y, Terayama K, Kanda A, Sugita K J Med Chem. 2024 Apr 11;67(7):5305-5314. doi: 10.1021/acs.jmedchem.3c01500. Epub , 2024 Mar 22. PMID:38517948<ref>PMID:38517948</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8wtr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Haginoya N]]
[[Category: Ishigai Y]]
[[Category: Kanda A]]
[[Category: Sugita K]]
[[Category: Suzuki M]]
[[Category: Terayama K]]