5dh5: Difference between revisions
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==PDE10 complexed with N-[(1-methylpyrazol-4-yl)methyl]-5-[[(1S,2S)-2-(2-pyridyl)cyclopropyl]methoxy]pyrazolo[1,5-a]pyrimidin-7-amine== | ==PDE10 complexed with N-[(1-methylpyrazol-4-yl)methyl]-5-[[(1S,2S)-2-(2-pyridyl)cyclopropyl]methoxy]pyrazolo[1,5-a]pyrimidin-7-amine== | ||
<StructureSection load='5dh5' size='340' side='right' caption='[[5dh5]], [[Resolution|resolution]] 2.00Å' scene=''> | <StructureSection load='5dh5' size='340' side='right'caption='[[5dh5]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5dh5]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DH5 OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5dh5]] 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=5DH5 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5DH5 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5AY:N-[(1-METHYL-1H-PYRAZOL-4-YL)METHYL]-5-{[(1S,2S)-2-(PYRIDIN-2-YL)CYCLOPROPYL]METHOXY}PYRAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>5AY</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=5AY:N-[(1-METHYL-1H-PYRAZOL-4-YL)METHYL]-5-{[(1S,2S)-2-(PYRIDIN-2-YL)CYCLOPROPYL]METHOXY}PYRAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>5AY</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">[[5dh4|5dh4]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5dh4|5dh4]]</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <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=9606 HUMAN])</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5dh5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dh5 OCA], [http://pdbe.org/5dh5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dh5 RCSB], [http://www.ebi.ac.uk/pdbsum/5dh5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dh5 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5dh5" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5dh5" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Yan, Y]] | [[Category: Yan, Y]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 11:03, 8 April 2020
PDE10 complexed with N-[(1-methylpyrazol-4-yl)methyl]-5-[[(1S,2S)-2-(2-pyridyl)cyclopropyl]methoxy]pyrazolo[1,5-a]pyrimidin-7-amine
Structural highlights
Function[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.[1] Publication Abstract from PubMedHerein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer. Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.,Raheem IT, Schreier JD, Fuerst J, Gantert L, Hostetler ED, Huszar S, Joshi A, Kandebo M, Kim SH, Li J, Ma B, McGaughey G, Sharma S, Shipe WD, Uslaner J, Vandeveer GH, Yan Y, Renger JJ, Smith SM, Coleman PJ, Cox CD Bioorg Med Chem Lett. 2016 Jan 1;26(1):126-32. doi: 10.1016/j.bmcl.2015.11.013., Epub 2015 Nov 10. PMID:26602277[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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