3snl

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Current revision (09:52, 1 March 2024) (edit) (undo)
 
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<StructureSection load='3snl' size='340' side='right'caption='[[3snl]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
<StructureSection load='3snl' size='340' side='right'caption='[[3snl]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3snl]] is a 2 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=3SNL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SNL FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3snl]] 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=3SNL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SNL FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=548:6-CHLORO-3,4-DIMETHYL-1-(3-METHYLPYRIDIN-4-YL)-8-(TRIFLUOROMETHYL)IMIDAZO[1,5-A]QUINOXALINE'>548</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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3sn7|3sn7]], [[3sni|3sni]]</div></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=548:6-CHLORO-3,4-DIMETHYL-1-(3-METHYLPYRIDIN-4-YL)-8-(TRIFLUOROMETHYL)IMIDAZO[1,5-A]QUINOXALINE'>548</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE10A ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3snl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3snl OCA], [https://pdbe.org/3snl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3snl RCSB], [https://www.ebi.ac.uk/pdbsum/3snl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3snl 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=3snl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3snl OCA], [https://pdbe.org/3snl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3snl RCSB], [https://www.ebi.ac.uk/pdbsum/3snl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3snl ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/PDE10_HUMAN PDE10_HUMAN]] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.<ref>PMID:17389385</ref>
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[https://www.uniprot.org/uniprot/PDE10_HUMAN PDE10_HUMAN] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.<ref>PMID:17389385</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.
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Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors.,Malamas MS, Ni Y, Erdei J, Stange H, Schindler R, Lankau HJ, Grunwald C, Fan KY, Parris K, Langen B, Egerland U, Hage T, Marquis KL, Grauer S, Brennan J, Navarra R, Graf R, Harrison BL, Robichaud A, Kronbach T, Pangalos MN, Hoefgen N, Brandon NJ J Med Chem. 2011 Oct 11. PMID:21988093<ref>PMID:21988093</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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<div class="pdbe-citations 3snl" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Brandon, N J]]
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[[Category: Brandon NJ]]
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[[Category: Brennan, J]]
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[[Category: Brennan J]]
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[[Category: Egerland, U]]
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[[Category: Egerland U]]
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[[Category: Erdei, J]]
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[[Category: Erdei J]]
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[[Category: Fan, K Y]]
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[[Category: Fan KY]]
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[[Category: Graf, R]]
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[[Category: Graf R]]
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[[Category: Grauer, S]]
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[[Category: Grauer S]]
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[[Category: Grunwald, C]]
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[[Category: Grunwald C]]
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[[Category: Hage, T]]
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[[Category: Hage T]]
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[[Category: Harrison, B L]]
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[[Category: Harrison BL]]
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[[Category: Hofgen, N]]
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[[Category: Hofgen N]]
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[[Category: Kronbach, T]]
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[[Category: Kronbach T]]
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[[Category: Langen, B]]
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[[Category: Langen B]]
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[[Category: Lankau, H J]]
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[[Category: Lankau H-J]]
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[[Category: Malamas, M S]]
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[[Category: Malamas MS]]
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[[Category: Marquis, K L]]
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[[Category: Marquis KL]]
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[[Category: Navarra, R]]
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[[Category: Navarra R]]
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[[Category: Ni, Y]]
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[[Category: Ni Y]]
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[[Category: Pangalos, M]]
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[[Category: Pangalos M]]
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[[Category: Parris, K D]]
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[[Category: Parris KD]]
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[[Category: Robichaud, A]]
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[[Category: Robichaud A]]
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[[Category: Schindler, R]]
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[[Category: Schindler R]]
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[[Category: Stange, H]]
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[[Category: Stange H]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase inhibitor]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Zn binding]]
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Current revision

Highly Potent, Selective, and Orally Active Phosphodiestarase 10A Inhibitors

PDB ID 3snl

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