5dh4
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | ''' | + | ==PDE10 complexed with 5-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine== |
| + | <StructureSection load='5dh4' size='340' side='right' caption='[[5dh4]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5dh4]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DH4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DH4 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4PX:3-(1-HYDROXY-2-METHYLPROPAN-2-YL)-5-PHENYL-3,5-DIHYDRO-1H-IMIDAZO[4,5-C][1,8]NAPHTHYRIDINE-2,4-DIONE'>4PX</scene>, <scene name='pdbligand=5AV:5-CHLORO-N-[(2,4-DIMETHYL-1,3-THIAZOL-5-YL)METHYL]PYRAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>5AV</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">[[5dh5|5dh5]]</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=5dh4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dh4 OCA], [http://pdbe.org/5dh4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dh4 RCSB], [http://www.ebi.ac.uk/pdbsum/5dh4 PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Herein, 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<ref>PMID:26602277</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 5dh4" style="background-color:#fffaf0;"></div> | |
| - | + | == References == | |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Yan, Y]] | [[Category: Yan, Y]] | ||
| + | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 02:15, 28 January 2016
PDE10 complexed with 5-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine
| |||||||||||
