4b05 - Revision history

OCA at 07:17, 1 May 2024

2024-05-01T07:17:03Z

←Older revision		Revision as of 07:17, 1 May 2024
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	<StructureSection load='4b05' size='340' side='right'caption='[[4b05]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='4b05' size='340' side='right'caption='[[4b05]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4b05]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B05 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B05 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4b05]] 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=4B05 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B05 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=32D:(1S)-1-[2-(DIFLUOROMETHYL)PYRIDIN-4-YL]-4-FLUORO-1-(3-PYRIMIDIN-5-YLPHENYL)-1H-ISOINDOL-3-AMINE'>32D</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene~~></td></tr>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.8Å</td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1fkn\|1fkn]], [[1m4h\|1m4h]], [[1py1\|1py1]], [[1sgz\|1sgz]], [[1tqf\|1tqf]], [[1ujj\|1ujj]], [[1ujk\|1ujk]], [[1w50\|1w50]], [[1w51\|1w51]], [[1xn2\|1xn2]], [[1xn3\|1xn3]], [[1xs7\|1xs7]], [[1ym2\|1ym2]], [[1ym4\|1ym4]], [[2b8l\|2b8l]], [[2b8v\|2b8v]], [[2fdp\|2fdp]], [[2va5\|2va5]], [[2va6\|2va6]], [[2va7\|2va7]], [[2vie\|2vie]], [[2vij\|2vij]], [[2viy\|2viy]], [[2viz\|2viz]], [[2vj6\|2vj6]], [[2vj7\|2vj7]], [[2vj9\|2vj9]], [[2vkm\|2vkm]], [[2vnm\|2vnm]], [[2vnn\|2vnn]], [[2wez\|2wez]], [[2wf0\|2wf0]], [[2wf1\|2wf1]], [[2wf2\|2wf2]], [[2wf3\|2wf3]], [[2wf4\|2wf4]], [[2wjo\|2wjo]], [[2xfi\|2xfi]], [[2xfj\|2xfj]], [[2xfk\|2xfk]], [[4acu\|4acu]], [[4acx\|4acx]], [[4azy\|4azy]], [[4b00\|4b00]]</div></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=32D:(1S)-1-[2-(DIFLUOROMETHYL)PYRIDIN-4-YL]-4-FLUORO-1-(3-PYRIMIDIN-5-YLPHENYL)-1H-ISOINDOL-3-AMINE'>32D</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=4b05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b05 OCA], [https://pdbe.org/4b05 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b05 RCSB], [https://www.ebi.ac.uk/pdbsum/4b05 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b05 ProSAT]</span></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=4b05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b05 OCA], [https://pdbe.org/4b05 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b05 RCSB], [https://www.ebi.ac.uk/pdbsum/4b05 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b05 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>	+	[https://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Beta-site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid beta peptide (Abeta) species. Since cerebral deposition of Abeta species might be critical for the pathogenesis of Alzheimers disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical FRET assay, Abeta and sAPPbeta release from modified and wild type human SH-SY5Y cells, mouse N2A cells, as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and Cathepsin D were 14 and >1000 fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain and CSF Abeta levels in mouse, guinea pig and non-human primate. Pharmacokinetic/ Pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduce the levels of Abeta in brain, CSF and plasma in several preclinical species. It might therefore have disease-modifying potential in the treatment of Alzheimers disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.	+
-		+
-	Discovery of AZD3839, a potent and selective BACE1 clinical candidate for the treatment of Alzheimers Disease.,Jeppsson F, Eketjall S, Janson J, Karlstrom S, Gustavsson S, Olsson LL, Radesater AC, Ploeger B, Cebers G, Kolmodin K, Swahn BM, von Berg S, Bueters T, Falting J J Biol Chem. 2012 Oct 9. PMID:23048024<ref>PMID:23048024</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 4b05" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Memapsin 2]]~~	+	[[Category: Bueters T]]
-	~~[[Category: Berg, S von]]~~	+	[[Category: Cebers G]]
-	[[Category: Bueters, T]]	+	[[Category: Eketjall S]]
-	[[Category: Cebers, G]]	+	[[Category: Falting J]]
-	[[Category: Eketjall, S]]	+	[[Category: Gustavsson S]]
-	[[Category: Falting, J]]	+	[[Category: Janson J]]
-	[[Category: Gustavsson, S]]	+	[[Category: Jeppsson F]]
-	[[Category: Janson, J]]	+	[[Category: Karlstrom S]]
-	[[Category: Jeppsson, F]]	+	[[Category: Kolmodin K]]
-	[[Category: Karlstrom, S]]	+	[[Category: Olsson LL]]
-	[[Category: Kolmodin, K]]	+	[[Category: Ploeger B]]
-	[[Category: Olsson~~, L L~~]]	+	[[Category: Radesater AC]]
-	[[Category: Ploeger, B]]	+	[[Category: Swahn BM]]
-	[[Category: Radesater~~, A C~~]]	+	[[Category: Von Berg S]]
-	[[Category: Swahn~~, B M~~]]	+
-	[[Category: ~~Alzheimer's disease]]~~	+
-	~~[[Category: Aminoisoindole]]~~	+
-	~~[[Category: Hydrolase~~]]	+

OCA at 05:52, 25 August 2022

2022-08-25T05:52:37Z

←Older revision		Revision as of 05:52, 25 August 2022
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	<StructureSection load='4b05' size='340' side='right'caption='[[4b05]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='4b05' size='340' side='right'caption='[[4b05]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4b05]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B05 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4B05 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4b05]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B05 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B05 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=32D:(1S)-1-[2-(DIFLUOROMETHYL)PYRIDIN-4-YL]-4-FLUORO-1-(3-PYRIMIDIN-5-YLPHENYL)-1H-ISOINDOL-3-AMINE'>32D</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=32D:(1S)-1-[2-(DIFLUOROMETHYL)PYRIDIN-4-YL]-4-FLUORO-1-(3-PYRIMIDIN-5-YLPHENYL)-1H-ISOINDOL-3-AMINE'>32D</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1fkn\|1fkn]], [[1m4h\|1m4h]], [[1py1\|1py1]], [[1sgz\|1sgz]], [[1tqf\|1tqf]], [[1ujj\|1ujj]], [[1ujk\|1ujk]], [[1w50\|1w50]], [[1w51\|1w51]], [[1xn2\|1xn2]], [[1xn3\|1xn3]], [[1xs7\|1xs7]], [[1ym2\|1ym2]], [[1ym4\|1ym4]], [[2b8l\|2b8l]], [[2b8v\|2b8v]], [[2fdp\|2fdp]], [[2va5\|2va5]], [[2va6\|2va6]], [[2va7\|2va7]], [[2vie\|2vie]], [[2vij\|2vij]], [[2viy\|2viy]], [[2viz\|2viz]], [[2vj6\|2vj6]], [[2vj7\|2vj7]], [[2vj9\|2vj9]], [[2vkm\|2vkm]], [[2vnm\|2vnm]], [[2vnn\|2vnn]], [[2wez\|2wez]], [[2wf0\|2wf0]], [[2wf1\|2wf1]], [[2wf2\|2wf2]], [[2wf3\|2wf3]], [[2wf4\|2wf4]], [[2wjo\|2wjo]], [[2xfi\|2xfi]], [[2xfj\|2xfj]], [[2xfk\|2xfk]], [[4acu\|4acu]], [[4acx\|4acx]], [[4azy\|4azy]], [[4b00\|4b00]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1fkn\|1fkn]], [[1m4h\|1m4h]], [[1py1\|1py1]], [[1sgz\|1sgz]], [[1tqf\|1tqf]], [[1ujj\|1ujj]], [[1ujk\|1ujk]], [[1w50\|1w50]], [[1w51\|1w51]], [[1xn2\|1xn2]], [[1xn3\|1xn3]], [[1xs7\|1xs7]], [[1ym2\|1ym2]], [[1ym4\|1ym4]], [[2b8l\|2b8l]], [[2b8v\|2b8v]], [[2fdp\|2fdp]], [[2va5\|2va5]], [[2va6\|2va6]], [[2va7\|2va7]], [[2vie\|2vie]], [[2vij\|2vij]], [[2viy\|2viy]], [[2viz\|2viz]], [[2vj6\|2vj6]], [[2vj7\|2vj7]], [[2vj9\|2vj9]], [[2vkm\|2vkm]], [[2vnm\|2vnm]], [[2vnn\|2vnn]], [[2wez\|2wez]], [[2wf0\|2wf0]], [[2wf1\|2wf1]], [[2wf2\|2wf2]], [[2wf3\|2wf3]], [[2wf4\|2wf4]], [[2wjo\|2wjo]], [[2xfi\|2xfi]], [[2xfj\|2xfj]], [[2xfk\|2xfk]], [[4acu\|4acu]], [[4acx\|4acx]], [[4azy\|4azy]], [[4b00\|4b00]]</div></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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://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=4b05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b05 OCA], [~~http~~://pdbe.org/4b05 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4b05 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4b05 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4b05 ProSAT]</span></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=4b05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b05 OCA], [https://pdbe.org/4b05 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b05 RCSB], [https://www.ebi.ac.uk/pdbsum/4b05 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b05 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>	+	[[https://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 17:16, 29 January 2020

2020-01-29T17:16:32Z

←Older revision		Revision as of 17:16, 29 January 2020
Line 1:		Line 1:

	==Preclinical characterization of AZD3839, a novel clinical candidate BACE1 inhibitor for the treatment of Alzheimer Disease==		==Preclinical characterization of AZD3839, a novel clinical candidate BACE1 inhibitor for the treatment of Alzheimer Disease==
-	<StructureSection load='4b05' size='340' side='right' caption='[[4b05]], [[Resolution\|resolution]] 1.80Å' scene=''>	+	<StructureSection load='4b05' size='340' side='right'caption='[[4b05]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4b05]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B05 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B05 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4b05]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B05 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B05 FirstGlance]. <br>
Line 20:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 4b05" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4b05" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Beta secretase 3D structures\|Beta secretase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 25:		Line 28:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Memapsin 2]]		[[Category: Memapsin 2]]
	[[Category: Berg, S von]]		[[Category: Berg, S von]]

OCA at 06:49, 15 February 2018

2018-02-15T06:49:53Z

←Older revision		Revision as of 06:49, 15 February 2018
Line 20:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 4b05" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4b05" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Beta secretase\|Beta secretase]]
	== References ==		== References ==
	<references/>		<references/>
Line 29:		Line 26:
	[[Category: Human]]		[[Category: Human]]
	[[Category: Memapsin 2]]		[[Category: Memapsin 2]]
-	[[Category: Berg, S ~~Von~~]]	+	[[Category: Berg, S von]]
	[[Category: Bueters, T]]		[[Category: Bueters, T]]
	[[Category: Cebers, G]]		[[Category: Cebers, G]]

OCA at 23:37, 4 August 2016

2016-08-04T23:37:35Z

←Older revision		Revision as of 23:37, 4 August 2016
Line 1:		Line 1:
		+
	==Preclinical characterization of AZD3839, a novel clinical candidate BACE1 inhibitor for the treatment of Alzheimer Disease==		==Preclinical characterization of AZD3839, a novel clinical candidate BACE1 inhibitor for the treatment of Alzheimer Disease==
	<StructureSection load='4b05' size='340' side='right' caption='[[4b05]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='4b05' size='340' side='right' caption='[[4b05]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4b05]] 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=4B05 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B05 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4b05]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B05 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B05 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=32D:(1S)-1-[2-(DIFLUOROMETHYL)PYRIDIN-4-YL]-4-FLUORO-1-(3-PYRIMIDIN-5-YLPHENYL)-1H-ISOINDOL-3-AMINE'>32D</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=32D:(1S)-1-[2-(DIFLUOROMETHYL)PYRIDIN-4-YL]-4-FLUORO-1-(3-PYRIMIDIN-5-YLPHENYL)-1H-ISOINDOL-3-AMINE'>32D</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1fkn\|1fkn]], [[1m4h\|1m4h]], [[1py1\|1py1]], [[1sgz\|1sgz]], [[1tqf\|1tqf]], [[1ujj\|1ujj]], [[1ujk\|1ujk]], [[1w50\|1w50]], [[1w51\|1w51]], [[1xn2\|1xn2]], [[1xn3\|1xn3]], [[1xs7\|1xs7]], [[1ym2\|1ym2]], [[1ym4\|1ym4]], [[2b8l\|2b8l]], [[2b8v\|2b8v]], [[2fdp\|2fdp]], [[2va5\|2va5]], [[2va6\|2va6]], [[2va7\|2va7]], [[2vie\|2vie]], [[2vij\|2vij]], [[2viy\|2viy]], [[2viz\|2viz]], [[2vj6\|2vj6]], [[2vj7\|2vj7]], [[2vj9\|2vj9]], [[2vkm\|2vkm]], [[2vnm\|2vnm]], [[2vnn\|2vnn]], [[2wez\|2wez]], [[2wf0\|2wf0]], [[2wf1\|2wf1]], [[2wf2\|2wf2]], [[2wf3\|2wf3]], [[2wf4\|2wf4]], [[2wjo\|2wjo]], [[2xfi\|2xfi]], [[2xfj\|2xfj]], [[2xfk\|2xfk]], [[4acu\|4acu]], [[4acx\|4acx]], [[4azy\|4azy]], [[4b00\|4b00]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1fkn\|1fkn]], [[1m4h\|1m4h]], [[1py1\|1py1]], [[1sgz\|1sgz]], [[1tqf\|1tqf]], [[1ujj\|1ujj]], [[1ujk\|1ujk]], [[1w50\|1w50]], [[1w51\|1w51]], [[1xn2\|1xn2]], [[1xn3\|1xn3]], [[1xs7\|1xs7]], [[1ym2\|1ym2]], [[1ym4\|1ym4]], [[2b8l\|2b8l]], [[2b8v\|2b8v]], [[2fdp\|2fdp]], [[2va5\|2va5]], [[2va6\|2va6]], [[2va7\|2va7]], [[2vie\|2vie]], [[2vij\|2vij]], [[2viy\|2viy]], [[2viz\|2viz]], [[2vj6\|2vj6]], [[2vj7\|2vj7]], [[2vj9\|2vj9]], [[2vkm\|2vkm]], [[2vnm\|2vnm]], [[2vnn\|2vnn]], [[2wez\|2wez]], [[2wf0\|2wf0]], [[2wf1\|2wf1]], [[2wf2\|2wf2]], [[2wf3\|2wf3]], [[2wf4\|2wf4]], [[2wjo\|2wjo]], [[2xfi\|2xfi]], [[2xfj\|2xfj]], [[2xfk\|2xfk]], [[4acu\|4acu]], [[4acx\|4acx]], [[4azy\|4azy]], [[4b00\|4b00]]</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='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=4b05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b05 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4b05 RCSB], [http://www.ebi.ac.uk/pdbsum/4b05 PDBsum]</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=4b05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b05 OCA], [http://pdbe.org/4b05 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4b05 RCSB], [http://www.ebi.ac.uk/pdbsum/4b05 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4b05 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4b05" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 25:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Memapsin 2]]		[[Category: Memapsin 2]]
	[[Category: Berg, S Von]]		[[Category: Berg, S Von]]

OCA at 14:02, 25 December 2014

2014-12-25T14:02:53Z

←Older revision		Revision as of 14:02, 25 December 2014
Line 1:		Line 1:
-	[[~~Image:~~4b05.~~png~~\|~~left~~\|~~200px~~]]	+	==Preclinical characterization of AZD3839, a novel clinical candidate BACE1 inhibitor for the treatment of Alzheimer Disease==
		+	<StructureSection load='4b05' size='340' side='right' caption='[[4b05]], [[Resolution\|resolution]] 1.80Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4b05]] 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=4B05 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B05 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=32D:(1S)-1-[2-(DIFLUOROMETHYL)PYRIDIN-4-YL]-4-FLUORO-1-(3-PYRIMIDIN-5-YLPHENYL)-1H-ISOINDOL-3-AMINE'>32D</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1fkn\|1fkn]], [[1m4h\|1m4h]], [[1py1\|1py1]], [[1sgz\|1sgz]], [[1tqf\|1tqf]], [[1ujj\|1ujj]], [[1ujk\|1ujk]], [[1w50\|1w50]], [[1w51\|1w51]], [[1xn2\|1xn2]], [[1xn3\|1xn3]], [[1xs7\|1xs7]], [[1ym2\|1ym2]], [[1ym4\|1ym4]], [[2b8l\|2b8l]], [[2b8v\|2b8v]], [[2fdp\|2fdp]], [[2va5\|2va5]], [[2va6\|2va6]], [[2va7\|2va7]], [[2vie\|2vie]], [[2vij\|2vij]], [[2viy\|2viy]], [[2viz\|2viz]], [[2vj6\|2vj6]], [[2vj7\|2vj7]], [[2vj9\|2vj9]], [[2vkm\|2vkm]], [[2vnm\|2vnm]], [[2vnn\|2vnn]], [[2wez\|2wez]], [[2wf0\|2wf0]], [[2wf1\|2wf1]], [[2wf2\|2wf2]], [[2wf3\|2wf3]], [[2wf4\|2wf4]], [[2wjo\|2wjo]], [[2xfi\|2xfi]], [[2xfj\|2xfj]], [[2xfk\|2xfk]], [[4acu\|4acu]], [[4acx\|4acx]], [[4azy\|4azy]], [[4b00\|4b00]]</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=4b05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b05 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4b05 RCSB], [http://www.ebi.ac.uk/pdbsum/4b05 PDBsum]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Beta-site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid beta peptide (Abeta) species. Since cerebral deposition of Abeta species might be critical for the pathogenesis of Alzheimers disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical FRET assay, Abeta and sAPPbeta release from modified and wild type human SH-SY5Y cells, mouse N2A cells, as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and Cathepsin D were 14 and >1000 fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain and CSF Abeta levels in mouse, guinea pig and non-human primate. Pharmacokinetic/ Pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduce the levels of Abeta in brain, CSF and plasma in several preclinical species. It might therefore have disease-modifying potential in the treatment of Alzheimers disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.

-	~~{{STRUCTURE_4b05\| PDB=4b05 \| SCENE= }}~~	+	Discovery of AZD3839, a potent and selective BACE1 clinical candidate for the treatment of Alzheimers Disease.,Jeppsson F, Eketjall S, Janson J, Karlstrom S, Gustavsson S, Olsson LL, Radesater AC, Ploeger B, Cebers G, Kolmodin K, Swahn BM, von Berg S, Bueters T, Falting J J Biol Chem. 2012 Oct 9. PMID:23048024<ref>PMID:23048024</ref>

-	~~===Preclinical characterization of AZD3839~~, a ~~novel clinical candidate BACE1 inhibitor for~~ the ~~treatment~~ of ~~Alzheimer Disease===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>

-	~~{{ABSTRACT_PUBMED_23048024}}~~	+	==See Also==
-		+	*[[Beta secretase\|Beta secretase]]
-	==~~About this Structure~~==	+	== References ==
-	[[~~4b05~~]] ~~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=4B05 OCA].~~	+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Memapsin 2]]		[[Category: Memapsin 2]]
-	[[Category: Berg, S Von.]]	+	[[Category: Berg, S Von]]
-	[[Category: Bueters, T.]]	+	[[Category: Bueters, T]]
-	[[Category: Cebers, G.]]	+	[[Category: Cebers, G]]
-	[[Category: Eketjall, S.]]	+	[[Category: Eketjall, S]]
-	[[Category: Falting, J.]]	+	[[Category: Falting, J]]
-	[[Category: Gustavsson, S.]]	+	[[Category: Gustavsson, S]]
-	[[Category: Janson, J.]]	+	[[Category: Janson, J]]
-	[[Category: Jeppsson, F.]]	+	[[Category: Jeppsson, F]]
-	[[Category: Karlstrom, S.]]	+	[[Category: Karlstrom, S]]
-	[[Category: Kolmodin, K.]]	+	[[Category: Kolmodin, K]]
-	[[Category: Olsson, L L.]]	+	[[Category: Olsson, L L]]
-	[[Category: Ploeger, B.]]	+	[[Category: Ploeger, B]]
-	[[Category: Radesater, A C.]]	+	[[Category: Radesater, A C]]
-	[[Category: Swahn, B M.]]	+	[[Category: Swahn, B M]]
	[[Category: Alzheimer's disease]]		[[Category: Alzheimer's disease]]
	[[Category: Aminoisoindole]]		[[Category: Aminoisoindole]]
	[[Category: Hydrolase]]		[[Category: Hydrolase]]

OCA at 06:20, 24 October 2012

2012-10-24T06:20:03Z

←Older revision		Revision as of 06:20, 24 October 2012
Line 1:		Line 1:
-	[[Image:4b05.~~jpg~~\|left\|200px]]	+	[[Image:4b05.png\|left\|200px]]

	{{STRUCTURE_4b05\| PDB=4b05 \| SCENE= }}		{{STRUCTURE_4b05\| PDB=4b05 \| SCENE= }}
Line 5:		Line 5:
	===Preclinical characterization of AZD3839, a novel clinical candidate BACE1 inhibitor for the treatment of Alzheimer Disease===		===Preclinical characterization of AZD3839, a novel clinical candidate BACE1 inhibitor for the treatment of Alzheimer Disease===

		+	{{ABSTRACT_PUBMED_23048024}}

	==About this Structure==		==About this Structure==

OCA at 07:10, 17 October 2012

2012-10-17T07:10:19Z

←Older revision		Revision as of 07:10, 17 October 2012
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:4b05.jpg\|left\|200px]]

-	~~The entry~~ 4b05 ~~is ON HOLD~~ ~~until Paper Publication~~	+	{{STRUCTURE_4b05\| PDB=4b05 \| SCENE= }}

-	~~Authors: Jeppsson~~, ~~F., Eketjall, S., Janson, J., Karlstrom, S., Gustavsson, S., Olsson, L.L., Radesater, A., Ploeger, B., Cebers, G., Kolmodin, K., Swahn, B., vonBerg, S., Bueters, T., Falting, J.~~	+	===Preclinical characterization of AZD3839, a novel clinical candidate BACE1 inhibitor for the treatment of Alzheimer Disease===

-	~~Description~~: ~~Preclinical characterization of AZD3839~~, ~~a novel clinical candidate BACE1 inhibitor for the treatment of~~ Alzheimer ~~Disease~~	+
		+	==About this Structure==
		+	[[4b05]] 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=4B05 OCA].
		+	[[Category: Homo sapiens]]
		+	[[Category: Memapsin 2]]
		+	[[Category: Berg, S Von.]]
		+	[[Category: Bueters, T.]]
		+	[[Category: Cebers, G.]]
		+	[[Category: Eketjall, S.]]
		+	[[Category: Falting, J.]]
		+	[[Category: Gustavsson, S.]]
		+	[[Category: Janson, J.]]
		+	[[Category: Jeppsson, F.]]
		+	[[Category: Karlstrom, S.]]
		+	[[Category: Kolmodin, K.]]
		+	[[Category: Olsson, L L.]]
		+	[[Category: Ploeger, B.]]
		+	[[Category: Radesater, A C.]]
		+	[[Category: Swahn, B M.]]
		+	[[Category: Alzheimer's disease]]
		+	[[Category: Aminoisoindole]]
		+	[[Category: Hydrolase]]

OCA at 07:41, 11 July 2012

2012-07-11T07:41:10Z

←Older revision		Revision as of 07:41, 11 July 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4b05 is ON HOLD	+	The entry 4b05 is ON HOLD until Paper Publication

	Authors: Jeppsson, F., Eketjall, S., Janson, J., Karlstrom, S., Gustavsson, S., Olsson, L.L., Radesater, A., Ploeger, B., Cebers, G., Kolmodin, K., Swahn, B., vonBerg, S., Bueters, T., Falting, J.		Authors: Jeppsson, F., Eketjall, S., Janson, J., Karlstrom, S., Gustavsson, S., Olsson, L.L., Radesater, A., Ploeger, B., Cebers, G., Kolmodin, K., Swahn, B., vonBerg, S., Bueters, T., Falting, J.

	Description: Preclinical characterization of AZD3839, a novel clinical candidate BACE1 inhibitor for the treatment of Alzheimer Disease		Description: Preclinical characterization of AZD3839, a novel clinical candidate BACE1 inhibitor for the treatment of Alzheimer Disease

OCA: Protected "4b05" [edit=sysop:move=sysop]

2012-07-04T07:09:32Z

Protected "4b05" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:09, 4 July 2012