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3sni

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Revision as of 20:20, 4 August 2016

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

Structural highlights

3sni 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:	3sn7, 3snl
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

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.

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^[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
↑ 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. Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors. J Med Chem. 2011 Oct 11. PMID:21988093 doi:10.1021/jm2009138

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3sni"

@@ Line 1: / Line 1: @@
 ==Highly Potent, Selective, and Orally Active Phosphodiestarase 10A Inhibitors==
 <StructureSection load='3sni' size='340' side='right' caption='[[3sni]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3sni]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SNI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SNI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3sni]] 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=3SNI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SNI FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=546:2-METHOXY-6,7-DIMETHYL-9-(4-METHYLPYRIDIN-3-YL)IMIDAZO[1,5-A]PYRIDO[3,2-E]PYRAZINE'>546</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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">[[3sn7|3sn7]], [[3snl|3snl]]</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 Homo sapiens])</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=3sni FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sni OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sni RCSB], [http://www.ebi.ac.uk/pdbsum/3sni PDBsum]</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=3sni FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sni OCA], [http://pdbe.org/3sni PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3sni RCSB], [http://www.ebi.ac.uk/pdbsum/3sni PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3sni ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3sni" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 25: / Line 27: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Brandon, N J]]
 [[Category: Brennan, J]]

3sni

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Revision as of 20:20, 4 August 2016

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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