3rsx: Difference between revisions
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==Structure of Bace-1 (Beta-Secretase) in Complex with 6-(Thiophen-3-yl)quinolin-2-amine== | |||
<StructureSection load='3rsx' size='340' side='right'caption='[[3rsx]], [[Resolution|resolution]] 2.48Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3rsx]] 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=3RSX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RSX 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]] 2.48Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=RSV:6-(THIOPHEN-3-YL)QUINOLIN-2-AMINE'>RSV</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=3rsx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rsx OCA], [https://pdbe.org/3rsx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3rsx RCSB], [https://www.ebi.ac.uk/pdbsum/3rsx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3rsx ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Using fragment-based screening of a focused fragment library, 2-aminoquinoline 1 was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2' binding pocket of BACE1 and enhancing the ligand's potency. We were able to improve the BACE1 potency to subnanomolar range, over 10(6)-fold more potent than the initial hit (900 muM). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood-brain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC(50) value of 11 nM on BACE1 and cellular activity of 80 nM. This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of Abeta levels in cerebrospinal fluid (CSF). | |||
From Fragment Screening to In Vivo Efficacy: Optimization of a Series of 2-Aminoquinolines as Potent Inhibitors of Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1).,Cheng Y, Judd TC, Bartberger MD, Brown J, Chen K, Fremeau RT, Hickman D, Hitchcock SA, Jordan B, Li V, Lopez P, Louie SW, Luo Y, Michelsen K, Nixey T, Powers TS, Rattan C, Sickmier EA, St Jean DJ, Wahl RC, Wen PH, Wood S J Med Chem. 2011 Aug 25;54(16):5836-57. Epub 2011 Jul 29. PMID:21707077<ref>PMID:21707077</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3rsx" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Beta secretase|Beta secretase]] | *[[Beta secretase 3D structures|Beta secretase 3D structures]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Sickmier | [[Category: Sickmier EA]] | ||