4y87 - Revision history

OCA at 13:02, 1 March 2024

OCA — Fri, 01 Mar 2024 13:02:48 GMT

←Older revision		Revision as of 13:02, 1 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4y87]] 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=4Y87 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y87 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4y87]] 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=4Y87 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y87 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=49E:6-{[(1R)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49E</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 3.1Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=49E:6-{[(1R)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49E</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4y87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y87 OCA], [https://pdbe.org/4y87 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y87 RCSB], [https://www.ebi.ac.uk/pdbsum/4y87 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y87 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=4y87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y87 OCA], [https://pdbe.org/4y87 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y87 RCSB], [https://www.ebi.ac.uk/pdbsum/4y87 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y87 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/PDE9A_HUMAN PDE9A_HUMAN] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.<ref>PMID:18757755</ref>		[https://www.uniprot.org/uniprot/PDE9A_HUMAN PDE9A_HUMAN] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.<ref>PMID:18757755</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazo lo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.
-
-	Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.,Huang M, Shao Y, Hou J, Cui W, Liang B, Huang Y, Li Z, Wu Y, Zhu X, Liu P, Wan Y, Ke H, Luo HB Mol Pharmacol. 2015 Nov;88(5):836-45. doi: 10.1124/mol.115.099747. Epub 2015 Aug , 27. PMID:26316540<ref>PMID:26316540</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4y87" style="background-color:#fffaf0;"></div>

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

OCA at 08:02, 3 May 2023

OCA — Wed, 03 May 2023 08:02:30 GMT

←Older revision		Revision as of 08:02, 3 May 2023
Line 3:		Line 3:
	<StructureSection load='4y87' size='340' side='right'caption='[[4y87]], [[Resolution\|resolution]] 3.10Å' scene=''>		<StructureSection load='4y87' size='340' side='right'caption='[[4y87]], [[Resolution\|resolution]] 3.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4y87]] 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=4Y87 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4Y87 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4y87]] 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=4Y87 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y87 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=49E:6-{[(1R)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49E</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=49E:6-{[(1R)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49E</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4y86\|4y86]]</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=4y87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y87 OCA], [https://pdbe.org/4y87 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y87 RCSB], [https://www.ebi.ac.uk/pdbsum/4y87 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y87 ProSAT]</span></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDE9A ([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/3',5'-cyclic-GMP_phosphodiesterase 3',5'-cyclic-GMP phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.35 3.1.4.35] </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=4y87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y87 OCA], [~~http~~://pdbe.org/4y87 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4y87 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4y87 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4y87 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/PDE9A_HUMAN PDE9A_HUMAN]] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.<ref>PMID:18757755</ref>	+	[https://www.uniprot.org/uniprot/PDE9A_HUMAN PDE9A_HUMAN] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.<ref>PMID:18757755</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 28:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~3',5'-cyclic-GMP phosphodiesterase]]~~	+	[[Category: Homo sapiens]]
-	~~[[Category: Human~~]]	+
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Huang, M]]	+	[[Category: Huang M]]
-	~~[[Category: Enantiomeric differentiation]]~~	+
-	~~[[Category: Hydrolase-hydrolase inhibitor complex]]~~	+
-	~~[[Category: Inhibitor selectivity pocket]]~~	+
-	~~[[Category: Pharmacokinetic]]~~	+
-	~~[[Category: Phosphodiesterase 9a~~]]	+

OCA at 10:44, 25 December 2019

OCA — Wed, 25 Dec 2019 10:44:38 GMT

←Older revision		Revision as of 10:44, 25 December 2019
Line 1:		Line 1:

	==Crystal structure of phosphodiesterase 9 in complex with (R)-C33 (6-{[(1R)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one)==		==Crystal structure of phosphodiesterase 9 in complex with (R)-C33 (6-{[(1R)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one)==
-	<StructureSection load='4y87' size='340' side='right' caption='[[4y87]], [[Resolution\|resolution]] 3.10Å' scene=''>	+	<StructureSection load='4y87' size='340' side='right'caption='[[4y87]], [[Resolution\|resolution]] 3.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4y87]] 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=4Y87 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y87 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4y87]] 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=4Y87 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y87 FirstGlance]. <br>
Line 21:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 4y87" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4y87" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Phosphodiesterase 3D structures\|Phosphodiesterase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 27:		Line 30:
	[[Category: 3',5'-cyclic-GMP phosphodiesterase]]		[[Category: 3',5'-cyclic-GMP phosphodiesterase]]
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Huang, M]]		[[Category: Huang, M]]
	[[Category: Enantiomeric differentiation]]		[[Category: Enantiomeric differentiation]]

OCA at 15:41, 15 November 2017

OCA — Wed, 15 Nov 2017 15:41:52 GMT

←Older revision		Revision as of 15:41, 15 November 2017
Line 1:		Line 1:
		+
	==Crystal structure of phosphodiesterase 9 in complex with (R)-C33 (6-{[(1R)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one)==		==Crystal structure of phosphodiesterase 9 in complex with (R)-C33 (6-{[(1R)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one)==
	<StructureSection load='4y87' size='340' side='right' caption='[[4y87]], [[Resolution\|resolution]] 3.10Å' scene=''>		<StructureSection load='4y87' size='340' side='right' caption='[[4y87]], [[Resolution\|resolution]] 3.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4y87]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y87 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y87 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4y87]] 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=4Y87 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y87 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=49E:6-{[(1R)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49E</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=49E:6-{[(1R)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49E</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4y86\|4y86]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4y86\|4y86]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDE9A ([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/3',5'-cyclic-GMP_phosphodiesterase 3',5'-cyclic-GMP phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.35 3.1.4.35] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3',5'-cyclic-GMP_phosphodiesterase 3',5'-cyclic-GMP phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.35 3.1.4.35] </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=4y87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y87 OCA], [http://pdbe.org/4y87 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y87 RCSB], [http://www.ebi.ac.uk/pdbsum/4y87 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=4y87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y87 OCA], [http://pdbe.org/4y87 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y87 RCSB], [http://www.ebi.ac.uk/pdbsum/4y87 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4y87 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 24:		Line 26:
	</StructureSection>		</StructureSection>
	[[Category: 3',5'-cyclic-GMP phosphodiesterase]]		[[Category: 3',5'-cyclic-GMP phosphodiesterase]]
		+	[[Category: Human]]
	[[Category: Huang, M]]		[[Category: Huang, M]]
	[[Category: Enantiomeric differentiation]]		[[Category: Enantiomeric differentiation]]

OCA at 21:50, 15 October 2015

OCA — Thu, 15 Oct 2015 21:50:47 GMT

←Older revision		Revision as of 21:50, 15 October 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Crystal structure of phosphodiesterase 9 in complex with (R)-C33 (6-{[(1R)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one)==
		+	<StructureSection load='4y87' size='340' side='right' caption='[[4y87]], [[Resolution\|resolution]] 3.10Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4y87]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y87 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y87 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=49E:6-{[(1R)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49E</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4y86\|4y86]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3',5'-cyclic-GMP_phosphodiesterase 3',5'-cyclic-GMP phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.35 3.1.4.35] </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=4y87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y87 OCA], [http://pdbe.org/4y87 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y87 RCSB], [http://www.ebi.ac.uk/pdbsum/4y87 PDBsum]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PDE9A_HUMAN PDE9A_HUMAN]] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.<ref>PMID:18757755</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazo lo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.

-	~~The entry 4y87 is ON HOLD until Paper Publication~~	+	Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.,Huang M, Shao Y, Hou J, Cui W, Liang B, Huang Y, Li Z, Wu Y, Zhu X, Liu P, Wan Y, Ke H, Luo HB Mol Pharmacol. 2015 Nov;88(5):836-45. doi: 10.1124/mol.115.099747. Epub 2015 Aug , 27. PMID:26316540<ref>PMID:26316540</ref>

-	~~Authors: Huang~~, M.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description: Crystal structure of phosphodiesterase 9 in complex with (R)~~-~~C33 (6~~-{[~~(1R)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo~~[3,4-~~d]pyrimidin~~-~~4-one)~~	+	<div class="pdbe-citations 4y87" style="background-color:#fffaf0;"></div>
-	~~[[Category: Unreleased Structures~~]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: 3',5'-cyclic-GMP phosphodiesterase]]
	[[Category: Huang, M]]		[[Category: Huang, M]]
		+	[[Category: Enantiomeric differentiation]]
		+	[[Category: Hydrolase-hydrolase inhibitor complex]]
		+	[[Category: Inhibitor selectivity pocket]]
		+	[[Category: Pharmacokinetic]]
		+	[[Category: Phosphodiesterase 9a]]

OCA at 10:23, 11 March 2015

OCA — Wed, 11 Mar 2015 10:23:04 GMT

←Older revision		Revision as of 10:23, 11 March 2015
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4y87 is ON HOLD	+	The entry 4y87 is ON HOLD until Paper Publication

	Authors: Huang, M.		Authors: Huang, M.

OCA: Protected "4y87" [edit=sysop:move=sysop]

OCA — Wed, 25 Feb 2015 12:47:48 GMT

Protected "4y87" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:47, 25 February 2015

OCA: New page: '''Unreleased structure''' The entry 4y87 is ON HOLD Authors: Huang, M. Description: Crystal structure of phosphodiesterase 9 in complex with (R)-C33 (6-{[(1R)-1-(4-chlorophenyl)ethyl]...

OCA — Wed, 25 Feb 2015 12:47:47 GMT

New page: '''Unreleased structure''' The entry 4y87 is ON HOLD Authors: Huang, M. Description: Crystal structure of phosphodiesterase 9 in complex with (R)-C33 (6-{[(1R)-1-(4-chlorophenyl)ethyl]...

New page

'''Unreleased structure'''

The entry 4y87 is ON HOLD

Authors: Huang, M.

Description: Crystal structure of phosphodiesterase 9 in complex with (R)-C33 (6-{[(1R)-1-(4-chlorophenyl)ethyl]amino}-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one)
[[Category: Unreleased Structures]]
[[Category: Huang, M]]