4h1e - Revision history

OCA at 16:01, 14 March 2024

OCA — Thu, 14 Mar 2024 16:01:44 GMT

←Older revision		Revision as of 16:01, 14 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4h1e]] is a 2 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=4H1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4H1E FirstGlance]. <br>		<table><tr><td colspan='2'>[[4h1e]] is a 2 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=4H1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4H1E FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=10J:3-{5-[(2E,4AR,7AR)-6-BENZOYL-2-IMINO-3-METHYL-4-OXOOCTAHYDRO-7AH-PYRROLO[3,4-D]PYRIMIDIN-7A-YL]THIOPHEN-3-YL}BENZONITRILE'>10J</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]] 1.9Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=10J:3-{5-[(2E,4AR,7AR)-6-BENZOYL-2-IMINO-3-METHYL-4-OXOOCTAHYDRO-7AH-PYRROLO[3,4-D]PYRIMIDIN-7A-YL]THIOPHEN-3-YL}BENZONITRILE'>10J</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=4h1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h1e OCA], [https://pdbe.org/4h1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4h1e RCSB], [https://www.ebi.ac.uk/pdbsum/4h1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4h1e 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=4h1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h1e OCA], [https://pdbe.org/4h1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4h1e RCSB], [https://www.ebi.ac.uk/pdbsum/4h1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4h1e 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 ==
-	On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2' binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2'. Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces Abeta(40) in the plasma, CSF, and cortex of rats in a dose-dependent manner.
-
-	Design and Validation of Bicyclic Iminopyrimidinones As Beta Amyloid Cleaving Enzyme-1 (BACE1) Inhibitors: Conformational Constraint to Favor a Bioactive Conformation.,Mandal M, Zhu Z, Cumming JN, Liu X, Strickland C, Mazzola RD, Caldwell JP, Leach P, Grzelak M, Hyde L, Zhang Q, Terracina G, Zhang L, Chen X, Kuvelkar R, Kennedy ME, Favreau L, Cox K, Orth P, Buevich A, Voigt J, Wang H, Kazakevich I, McKittrick BA, Greenlee W, Parker EM, Stamford AW J Med Chem. 2012 Oct 1. PMID:22989333<ref>PMID:22989333</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4h1e" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 07:52, 3 November 2022

OCA — Thu, 03 Nov 2022 07:52:35 GMT

←Older revision		Revision as of 07:52, 3 November 2022
Line 1:		Line 1:

	==Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexahydro-1H-pyrrolo[3,4-d]pyrimidin-2(3H)-iminium==		==Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexahydro-1H-pyrrolo[3,4-d]pyrimidin-2(3H)-iminium==
-	<StructureSection load='4h1e' size='340' side='right' caption='[[4h1e]], [[Resolution\|resolution]] 1.90Å' scene=''>	+	<StructureSection load='4h1e' size='340' side='right'caption='[[4h1e]], [[Resolution\|resolution]] 1.90Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4h1e]] is a 2 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=4H1E OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4H1E FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4h1e]] is a 2 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=4H1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4H1E FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=10J:3-{5-[(2E,4AR,7AR)-6-BENZOYL-2-IMINO-3-METHYL-4-OXOOCTAHYDRO-7AH-PYRROLO[3,4-D]PYRIMIDIN-7A-YL]THIOPHEN-3-YL}BENZONITRILE'>10J</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=10J:3-{5-[(2E,4AR,7AR)-6-BENZOYL-2-IMINO-3-METHYL-4-OXOOCTAHYDRO-7AH-PYRROLO[3,4-D]PYRIMIDIN-7A-YL]THIOPHEN-3-YL}BENZONITRILE'>10J</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4h1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h1e OCA], [https://pdbe.org/4h1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4h1e RCSB], [https://www.ebi.ac.uk/pdbsum/4h1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4h1e ProSAT]</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=4h1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h1e OCA], [~~http~~://pdbe.org/4h1e PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4h1e RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4h1e PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4h1e 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 ==
Line 22:		Line 20:

	==See Also==		==See Also==
-	*[[Beta secretase\|Beta secretase]]	+	*[[Beta secretase 3D structures\|Beta secretase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Memapsin 2~~]]	+	[[Category: Large Structures]]
-	[[Category: Orth, P]]	+	[[Category: Orth P]]
-	~~[[Category: Alzheimer]]~~	+
-	~~[[Category: Bace1]]~~	+
-	~~[[Category: Hydrolase-hydrolase inhibitor complex]]~~	+
-	~~[[Category: Hydrolase/hydrolase inhibitor~~]]	+

OCA at 16:06, 4 August 2016

OCA — Thu, 04 Aug 2016 16:06:19 GMT

←Older revision		Revision as of 16:06, 4 August 2016
Line 1:		Line 1:
		+
	==Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexahydro-1H-pyrrolo[3,4-d]pyrimidin-2(3H)-iminium==		==Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexahydro-1H-pyrrolo[3,4-d]pyrimidin-2(3H)-iminium==
	<StructureSection load='4h1e' size='340' side='right' caption='[[4h1e]], [[Resolution\|resolution]] 1.90Å' scene=''>		<StructureSection load='4h1e' size='340' side='right' caption='[[4h1e]], [[Resolution\|resolution]] 1.90Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4h1e]] is a 2 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=4H1E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4H1E FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4h1e]] is a 2 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=4H1E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4H1E FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=10J:3-{5-[(2E,4AR,7AR)-6-BENZOYL-2-IMINO-3-METHYL-4-OXOOCTAHYDRO-7AH-PYRROLO[3,4-D]PYRIMIDIN-7A-YL]THIOPHEN-3-YL}BENZONITRILE'>10J</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=10J:3-{5-[(2E,4AR,7AR)-6-BENZOYL-2-IMINO-3-METHYL-4-OXOOCTAHYDRO-7AH-PYRROLO[3,4-D]PYRIMIDIN-7A-YL]THIOPHEN-3-YL}BENZONITRILE'>10J</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4h1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h1e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4h1e RCSB], [http://www.ebi.ac.uk/pdbsum/4h1e 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=4h1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h1e OCA], [http://pdbe.org/4h1e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4h1e RCSB], [http://www.ebi.ac.uk/pdbsum/4h1e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4h1e 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 4h1e" 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: Orth, P]]		[[Category: Orth, P]]

OCA at 16:50, 24 December 2014

OCA — Wed, 24 Dec 2014 16:50:34 GMT

←Older revision		Revision as of 16:50, 24 December 2014
Line 8:		Line 8:
	<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=4h1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h1e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4h1e RCSB], [http://www.ebi.ac.uk/pdbsum/4h1e 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=4h1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h1e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4h1e RCSB], [http://www.ebi.ac.uk/pdbsum/4h1e PDBsum]</span></td></tr>
	</table>		</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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 09:53, 10 December 2014

OCA — Wed, 10 Dec 2014 09:53:19 GMT

←Older revision		Revision as of 09:53, 10 December 2014
Line 1:		Line 1:
-	[[~~Image:~~4h1e.~~png~~\|~~left~~\|~~200px~~]]	+	==Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexahydro-1H-pyrrolo[3,4-d]pyrimidin-2(3H)-iminium==
		+	<StructureSection load='4h1e' size='340' side='right' caption='[[4h1e]], [[Resolution\|resolution]] 1.90Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4h1e]] is a 2 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=4H1E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4H1E FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=10J:3-{5-[(2E,4AR,7AR)-6-BENZOYL-2-IMINO-3-METHYL-4-OXOOCTAHYDRO-7AH-PYRROLO[3,4-D]PYRIMIDIN-7A-YL]THIOPHEN-3-YL}BENZONITRILE'>10J</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, 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=4h1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h1e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4h1e RCSB], [http://www.ebi.ac.uk/pdbsum/4h1e PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2' binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2'. Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces Abeta(40) in the plasma, CSF, and cortex of rats in a dose-dependent manner.

-	~~{{STRUCTURE_4h1e\| PDB=4h1e \| SCENE= }}~~	+	Design and Validation of Bicyclic Iminopyrimidinones As Beta Amyloid Cleaving Enzyme-1 (BACE1) Inhibitors: Conformational Constraint to Favor a Bioactive Conformation.,Mandal M, Zhu Z, Cumming JN, Liu X, Strickland C, Mazzola RD, Caldwell JP, Leach P, Grzelak M, Hyde L, Zhang Q, Terracina G, Zhang L, Chen X, Kuvelkar R, Kennedy ME, Favreau L, Cox K, Orth P, Buevich A, Voigt J, Wang H, Kazakevich I, McKittrick BA, Greenlee W, Parker EM, Stamford AW J Med Chem. 2012 Oct 1. PMID:22989333<ref>PMID:22989333</ref>

-	~~===Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexahydro-1H-pyrrolo[3~~,~~4-d]pyrimidin-2(3H)-iminium===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>

-	~~{{ABSTRACT_PUBMED_22989333}}~~	+	==See Also==
-		+	*[[Beta secretase\|Beta secretase]]
-	==~~About this Structure~~==	+	== References ==
-	[[~~4h1e~~]] ~~is a 2 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=4H1E OCA].~~	+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Memapsin 2]]		[[Category: Memapsin 2]]
-	[[Category: Orth, P.]]	+	[[Category: Orth, P]]
	[[Category: Alzheimer]]		[[Category: Alzheimer]]
	[[Category: Bace1]]		[[Category: Bace1]]
	[[Category: Hydrolase-hydrolase inhibitor complex]]		[[Category: Hydrolase-hydrolase inhibitor complex]]
	[[Category: Hydrolase/hydrolase inhibitor]]		[[Category: Hydrolase/hydrolase inhibitor]]

OCA at 10:42, 14 November 2012

OCA — Wed, 14 Nov 2012 10:42:51 GMT

←Older revision		Revision as of 10:42, 14 November 2012
Line 1:		Line 1:
-	[[Image:4h1e.~~jpg~~\|left\|200px]]	+	[[Image:4h1e.png\|left\|200px]]

	{{STRUCTURE_4h1e\| PDB=4h1e \| SCENE= }}		{{STRUCTURE_4h1e\| PDB=4h1e \| SCENE= }}

OCA at 07:05, 17 October 2012

OCA — Wed, 17 Oct 2012 07:05:52 GMT

←Older revision		Revision as of 07:05, 17 October 2012
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:4h1e.jpg\|left\|200px]]

-	~~The entry~~ 4h1e ~~is ON HOLD~~ ~~until Paper Publication~~	+	{{STRUCTURE_4h1e\| PDB=4h1e \| SCENE= }}

-	~~Authors: Orth~~, P.	+	===Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexahydro-1H-pyrrolo[3,4-d]pyrimidin-2(3H)-iminium===

-	~~Description:~~ Structure ~~of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-~~2-~~yl)-3-methyl-4-oxohexahydro-1H-pyrrolo~~[3,~~4-d~~]~~pyrimidin~~-~~2(3H)-iminium~~	+	{{ABSTRACT_PUBMED_22989333}}
		+
		+	==About this Structure==
		+	[[4h1e]] is a 2 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=4H1E OCA].
		+	[[Category: Homo sapiens]]
		+	[[Category: Memapsin 2]]
		+	[[Category: Orth, P.]]
		+	[[Category: Alzheimer]]
		+	[[Category: Bace1]]
		+	[[Category: Hydrolase-hydrolase inhibitor complex]]
		+	[[Category: Hydrolase/hydrolase inhibitor]]

OCA at 05:46, 3 October 2012

OCA — Wed, 03 Oct 2012 05:46:37 GMT

←Older revision		Revision as of 05:46, 3 October 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4h1e is ON HOLD	+	The entry 4h1e is ON HOLD until Paper Publication

	Authors: Orth, P.		Authors: Orth, P.

	Description: Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexahydro-1H-pyrrolo[3,4-d]pyrimidin-2(3H)-iminium		Description: Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexahydro-1H-pyrrolo[3,4-d]pyrimidin-2(3H)-iminium

OCA: Protected "4h1e" [edit=sysop:move=sysop]

OCA — Wed, 19 Sep 2012 06:57:24 GMT

Protected "4h1e" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:57, 19 September 2012

OCA: New page: '''Unreleased structure''' The entry 4h1e is ON HOLD Authors: Orth, P. Description: Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexah...

OCA — Wed, 19 Sep 2012 06:57:23 GMT

New page: '''Unreleased structure''' The entry 4h1e is ON HOLD Authors: Orth, P. Description: Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexah...

New page

'''Unreleased structure'''

The entry 4h1e is ON HOLD

Authors: Orth, P.

Description: Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexahydro-1H-pyrrolo[3,4-d]pyrimidin-2(3H)-iminium