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5axq

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Revision as of 13:59, 16 November 2017

Crystal structure of the catalytic domain of PDE10A complexed with highly potent and brain-penetrant PDE10A Inhibitor with 2-oxindole scaffold

Structural highlights

5axq is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	5axp
Gene:	PDE10A (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory activity (IC50=0.94nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyr idazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A inhibitory activity (IC50=0.080nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3mg/kg by oral administration in mice.

Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor.,Yoshikawa M, Kamisaki H, Kunitomo J, Oki H, Kokubo H, Suzuki A, Ikemoto T, Nakashima K, Kamiguchi N, Harada A, Kimura H, Taniguchi T Bioorg Med Chem. 2015 Nov 15;23(22):7138-49. doi: 10.1016/j.bmc.2015.10.002. Epub, 2015 Oct 9. PMID:26494583^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wang H, Liu Y, Hou J, Zheng M, Robinson H, Ke H. Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5782-7. Epub 2007 Mar 26. PMID:17389385
↑ Yoshikawa M, Kamisaki H, Kunitomo J, Oki H, Kokubo H, Suzuki A, Ikemoto T, Nakashima K, Kamiguchi N, Harada A, Kimura H, Taniguchi T. Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor. Bioorg Med Chem. 2015 Nov 15;23(22):7138-49. doi: 10.1016/j.bmc.2015.10.002. Epub, 2015 Oct 9. PMID:26494583 doi:http://dx.doi.org/10.1016/j.bmc.2015.10.002

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5axq"

Categories: Human | Oki, H | Zama, Y | Hydrolase-hydrolase inhibitor complex | Hydrolase/hydrolase inhibitor

@@ Line 1: / Line 1: @@
 ==Crystal structure of the catalytic domain of PDE10A complexed with highly potent and brain-penetrant PDE10A Inhibitor with 2-oxindole scaffold==
 <StructureSection load='5axq' size='340' side='right' caption='[[5axq]], [[Resolution|resolution]] 1.77&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5axq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AXQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AXQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5axq]] 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=5AXQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AXQ FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4LK:3-[3-FLUORANYL-4-[5-METHOXY-4-OXIDANYLIDENE-3-(2-PHENYLPYRAZOL-3-YL)PYRIDAZIN-1-YL]PHENYL]-1,3-OXAZOLIDIN-2-ONE'>4LK</scene>, <scene name='pdbligand=4LP:1-(CYCLOPROPYLMETHYL)-4-FLUORANYL-5-[5-METHOXY-4-OXIDANYLIDENE-3-(2-PHENYLPYRAZOL-3-YL)PYRIDAZIN-1-YL]-3,3-DIMETHYL-INDOL-2-ONE'>4LP</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">[[5axp|5axp]]</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=5axq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5axq OCA], [http://pdbe.org/5axq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5axq RCSB], [http://www.ebi.ac.uk/pdbsum/5axq PDBsum]</span></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=9606 HUMAN])</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=5axq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5axq OCA], [http://pdbe.org/5axq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5axq RCSB], [http://www.ebi.ac.uk/pdbsum/5axq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5axq ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Oki, H]]
 [[Category: Zama, Y]]
 [[Category: Hydrolase-hydrolase inhibitor complex]]
 [[Category: Hydrolase/hydrolase inhibitor]]

5axq

From Proteopedia

Revision as of 13:59, 16 November 2017

Crystal structure of the catalytic domain of PDE10A complexed with highly potent and brain-penetrant PDE10A Inhibitor with 2-oxindole scaffold

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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