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| | ==Discovery of novel inhibitors of PDE10A== | | ==Discovery of novel inhibitors of PDE10A== |
| - | <StructureSection load='3hr1' size='340' side='right' caption='[[3hr1]], [[Resolution|resolution]] 1.53Å' scene=''> | + | <StructureSection load='3hr1' size='340' side='right'caption='[[3hr1]], [[Resolution|resolution]] 1.53Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3hr1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HR1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3HR1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3hr1]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HR1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HR1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PF9:2-{[4-(1-METHYL-4-PYRIDIN-4-YL-1H-PYRAZOL-3-YL)PHENOXY]METHYL}QUINOLINE'>PF9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.53Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3hqw|3hqw]], [[3hqy|3hqy]], [[3hqz|3hqz]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PF9:2-{[4-(1-METHYL-4-PYRIDIN-4-YL-1H-PYRAZOL-3-YL)PHENOXY]METHYL}QUINOLINE'>PF9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Pde10a ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</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=3hr1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hr1 OCA], [https://pdbe.org/3hr1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hr1 RCSB], [https://www.ebi.ac.uk/pdbsum/3hr1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hr1 ProSAT]</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=3hr1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hr1 OCA], [http://pdbe.org/3hr1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3hr1 RCSB], [http://www.ebi.ac.uk/pdbsum/3hr1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3hr1 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PDE10_RAT PDE10_RAT]] 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:10583409</ref> | + | [https://www.uniprot.org/uniprot/PDE10_RAT PDE10_RAT] 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:10583409</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Phosphodiesterase|Phosphodiesterase]] | + | *[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| - | [[Category: Marr, E S]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Pandit, J]] | + | [[Category: Marr ES]] |
| - | [[Category: Allosteric enzyme]] | + | [[Category: Pandit J]] |
| - | [[Category: Alternative splicing]]
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| - | [[Category: Camp]]
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| - | [[Category: Camp-binding]]
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| - | [[Category: Cgmp]]
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| - | [[Category: Cgmp-binding]]
| + | |
| - | [[Category: Cytoplasm]]
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| - | [[Category: Hydrolase]]
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| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
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| - | [[Category: Magnesium]]
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| - | [[Category: Metal-binding]]
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| - | [[Category: Nucleotide-binding]]
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| - | [[Category: Pde 10a]]
| + | |
| - | [[Category: Pde10 inhibitor]]
| + | |
| - | [[Category: Phosphodiesterase 10a]]
| + | |
| - | [[Category: Zinc]]
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| Structural highlights
Function
PDE10_RAT 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.[1]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.
Discovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the Treatment of Schizophrenia (dagger) dagger Coordinates of the PDE10A crystal structures have been deposited in the Protein Data Bank for compound 1 (3HQW), 2 (3HQY), 3 (3HQW) and 9 (3HR1).,Verhoest PR, Chapin DS, Corman M, Fonseca K, Harms JF, Hou X, Marr ES, Menniti FS, Nelson F, O'Connor R, Pandit J, Proulx-Lafrance C, Schmidt AW, Schmidt CJ, Suiciak JA, Liras S J Med Chem. 2009 Jul 24. PMID:19630403[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Fujishige K, Kotera J, Omori K. Striatum- and testis-specific phosphodiesterase PDE10A isolation and characterization of a rat PDE10A. Eur J Biochem. 1999 Dec;266(3):1118-27. PMID:10583409
- ↑ Verhoest PR, Chapin DS, Corman M, Fonseca K, Harms JF, Hou X, Marr ES, Menniti FS, Nelson F, O'Connor R, Pandit J, Proulx-Lafrance C, Schmidt AW, Schmidt CJ, Suiciak JA, Liras S. Discovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the Treatment of Schizophrenia (dagger) dagger Coordinates of the PDE10A crystal structures have been deposited in the Protein Data Bank for compound 1 (3HQW), 2 (3HQY), 3 (3HQW) and 9 (3HR1). J Med Chem. 2009 Jul 24. PMID:19630403 doi:10.1021/jm900521k
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