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==Structure of Bace-1 (Beta-Secretase) in Complex with (2R)-N-((2S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-3-hydroxy-4-((S)-6'-neopentyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridine]-4'-ylamino)butan-2-yl)-2-methoxypropanamide== | |||
<StructureSection load='4dh6' size='340' side='right' caption='[[4dh6]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4dh6]] 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=4DH6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DH6 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0KN:(2R)-N-[(2S,3R)-1-(1,3-BENZODIOXOL-5-YL)-4-{[(4S)-6-(2,2-DIMETHYLPROPYL)-3,4-DIHYDROSPIRO[CYCLOBUTANE-1,2-PYRANO[2,3-B]PYRIDIN]-4-YL]AMINO}-3-HYDROXYBUTAN-2-YL]-2-METHOXYPROPANAMIDE'>0KN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></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=4dh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dh6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dh6 RCSB], [http://www.ebi.ac.uk/pdbsum/4dh6 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A series of potent hydroxyethyl amine (HEA) derived inhibitors of ss-site APP cleaving enzyme (BACE) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogs that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS ss-amyloid (Ass) in Sprague Dawley rats following oral administration. | |||
Design and preparation of a potent series of hydroxyethylamine containing beta-secretase inhibitors that demonstrate robust reduction of central ss-amyloid.,Weiss MM, Williamson T, Babu-Khan S, Bartberger MD, Brown J, Chen K, Cheng Y, Citron M, Croghan MD, Dineen TA, Esmay J, Graceffa RF, Harried S, Hickman D, Hitchcock SA, Horne DB, Huang H, Imbeah-Ampiah R, Judd T, Kaller MR, Kreiman CR, La DS, Li V, Lopez P, Louie S, Monenschein H, Nguyen TT, Pennington LD, Rattan C, San Miguel T, Sickmier EA, Wahl RC, Wen PH, Wood S, Xue Q, Yang BH, Patel VF, Zhong W J Med Chem. 2012 Apr 2. PMID:22468639<ref>PMID:22468639</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: Bace-1]] | [[Category: Bace-1]] | ||
[[Category: Beta-secretase]] | [[Category: Beta-secretase]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 12:17, 21 December 2014
Structure of Bace-1 (Beta-Secretase) in Complex with (2R)-N-((2S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-3-hydroxy-4-((S)-6'-neopentyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridine]-4'-ylamino)butan-2-yl)-2-methoxypropanamideStructure of Bace-1 (Beta-Secretase) in Complex with (2R)-N-((2S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-3-hydroxy-4-((S)-6'-neopentyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridine]-4'-ylamino)butan-2-yl)-2-methoxypropanamide
Structural highlights
Publication Abstract from PubMedA series of potent hydroxyethyl amine (HEA) derived inhibitors of ss-site APP cleaving enzyme (BACE) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogs that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS ss-amyloid (Ass) in Sprague Dawley rats following oral administration. Design and preparation of a potent series of hydroxyethylamine containing beta-secretase inhibitors that demonstrate robust reduction of central ss-amyloid.,Weiss MM, Williamson T, Babu-Khan S, Bartberger MD, Brown J, Chen K, Cheng Y, Citron M, Croghan MD, Dineen TA, Esmay J, Graceffa RF, Harried S, Hickman D, Hitchcock SA, Horne DB, Huang H, Imbeah-Ampiah R, Judd T, Kaller MR, Kreiman CR, La DS, Li V, Lopez P, Louie S, Monenschein H, Nguyen TT, Pennington LD, Rattan C, San Miguel T, Sickmier EA, Wahl RC, Wen PH, Wood S, Xue Q, Yang BH, Patel VF, Zhong W J Med Chem. 2012 Apr 2. PMID:22468639[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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