3rtm: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[ | ==Structure of Bace-1 (Beta-Secretase) in Complex with 3-(2-Aminoquinolin-3-yl)-N-cyclohexyl-N-methylpropanamide== | ||
<StructureSection load='3rtm' size='340' side='right' caption='[[3rtm]], [[Resolution|resolution]] 2.76Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3rtm]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RTM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3RTM FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=RTM:3-(2-AMINOQUINOLIN-3-YL)-N-CYCLOHEXYL-N-METHYLPROPANAMIDE'>RTM</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3rsv|3rsv]], [[3rsx|3rsx]], [[3rth|3rth]], [[3rtn|3rtn]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3rtm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rtm OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3rtm RCSB], [http://www.ebi.ac.uk/pdbsum/3rtm PDBsum]</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> | |||
==See Also== | ==See Also== | ||
*[[Beta secretase|Beta secretase]] | *[[Beta secretase|Beta secretase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Sickmier, E A | [[Category: Sickmier, E A]] | ||
[[Category: Aspartyl protease]] | [[Category: Aspartyl protease]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 14:43, 9 December 2014
Structure of Bace-1 (Beta-Secretase) in Complex with 3-(2-Aminoquinolin-3-yl)-N-cyclohexyl-N-methylpropanamideStructure of Bace-1 (Beta-Secretase) in Complex with 3-(2-Aminoquinolin-3-yl)-N-cyclohexyl-N-methylpropanamide
Structural highlights
Publication Abstract from PubMedUsing 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||||