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4g2j

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==Human pde9 in complex with selective compound==
==Human pde9 in complex with selective compound==
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<StructureSection load='4g2j' size='340' side='right' caption='[[4g2j]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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<StructureSection load='4g2j' size='340' side='right'caption='[[4g2j]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4g2j]] 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=4G2J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G2J FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4g2j]] 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=4G2J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G2J FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0WF:1-CYCLOPENTYL-6-[(1R)-1-(3-PHENOXYAZETIDIN-1-YL)ETHYL]-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>0WF</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</td></tr>
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<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 Homo sapiens])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0WF:1-CYCLOPENTYL-6-[(1R)-1-(3-PHENOXYAZETIDIN-1-YL)ETHYL]-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>0WF</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4g2j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g2j OCA], [https://pdbe.org/4g2j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g2j RCSB], [https://www.ebi.ac.uk/pdbsum/4g2j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g2j ProSAT]</span></td></tr>
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<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=4g2j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g2j OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4g2j RCSB], [http://www.ebi.ac.uk/pdbsum/4g2j PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[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>
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Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma &gt;/= 1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.
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Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors.,Claffey MM, Helal CJ, Verhoest PR, Kang Z, Fors KS, Jung S, Zhong J, Bundesmann MW, Hou X, Lui S, Kleiman RJ, Vanase-Frawley M, Schmidt AW, Menniti F, Schmidt CJ, Hoffman WE, Hajos M, McDowell L, O'Connor RE, Macdougall-Murphy M, Fonseca KR, Becker SL, Nelson FR, Liras S J Med Chem. 2012 Nov 8;55(21):9055-68. doi: 10.1021/jm3009635. Epub 2012 Oct 12. PMID:23025719<ref>PMID:23025719</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==See Also==
==See Also==
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*[[Phosphodiesterase|Phosphodiesterase]]
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*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: 3',5'-cyclic-GMP phosphodiesterase]]
 
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Liu, S]]
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[[Category: Large Structures]]
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[[Category: Cgmp->gmp]]
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[[Category: Liu S]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Inhibitor]]
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[[Category: Phosphodiesterase]]
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Current revision

Human pde9 in complex with selective compound

PDB ID 4g2j

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