4fcb

From Proteopedia

(Difference between revisions)

Revision as of 04:48, 7 October 2022

Potent and Selective Phosphodiesterase 10A Inhibitors

Structural highlights

4fcb is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
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 triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4nM), demonstrated high selectivity (>200x) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2mg/kg).

Novel triazines as potent and selective phosphodiesterase 10A inhibitors.,Malamas MS, Stange H, Schindler R, Lankau HJ, Grunwald C, Langen B, Egerland U, Hage T, Ni Y, Erdei J, Fan KY, Parris K, Marquis KL, Grauer S, Brennan J, Navarra R, Graf R, Harrison BL, Robichaud A, Kronbach T, Pangalos MN, Brandon NJ, Hoefgen N Bioorg Med Chem Lett. 2012 Sep 15;22(18):5876-84. Epub 2012 Jul 31. PMID:22902656^[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, Stange H, Schindler R, Lankau HJ, Grunwald C, Langen B, Egerland U, Hage T, Ni Y, Erdei J, Fan KY, Parris K, Marquis KL, Grauer S, Brennan J, Navarra R, Graf R, Harrison BL, Robichaud A, Kronbach T, Pangalos MN, Brandon NJ, Hoefgen N. Novel triazines as potent and selective phosphodiesterase 10A inhibitors. Bioorg Med Chem Lett. 2012 Sep 15;22(18):5876-84. Epub 2012 Jul 31. PMID:22902656 doi:http://dx.doi.org/10.1016/j.bmcl.2012.07.076

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/4fcb"

Categories: Homo sapiens | Large Structures | Parris KD

@@ Line 1: / Line 1: @@
 ==Potent and Selective Phosphodiesterase 10A Inhibitors==
-<StructureSection load='4fcb' size='340' side='right' caption='[[4fcb]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+<StructureSection load='4fcb' size='340' side='right'caption='[[4fcb]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4fcb]] 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=4FCB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FCB FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4fcb]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FCB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FCB FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0T7:3,4-DIMETHYL-1-PROPYL-7-(QUINOLIN-2-YLMETHOXY)IMIDAZO[1,5-A]QUINOXALINE'>0T7</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=0T7:3,4-DIMETHYL-1-PROPYL-7-(QUINOLIN-2-YLMETHOXY)IMIDAZO[1,5-A]QUINOXALINE'>0T7</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">[[4fcd|4fcd]]</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=4fcb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fcb OCA], [https://pdbe.org/4fcb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fcb RCSB], [https://www.ebi.ac.uk/pdbsum/4fcb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fcb ProSAT]</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=4fcb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fcb OCA], [http://pdbe.org/4fcb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4fcb RCSB], [http://www.ebi.ac.uk/pdbsum/4fcb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4fcb ProSAT]</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>
+[https://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 ==
@@ Line 20: / Line 18: @@
 </div>
 <div class="pdbe-citations 4fcb" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Parris, K D]]
+[[Category: Large Structures]]
-[[Category: Binding site]]
+[[Category: Parris KD]]
-[[Category: Cyclic amp]]
-[[Category: Cyclic gmp]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Ligand]]
-[[Category: Phosphodiesterase inhibitor]]

4fcb

From Proteopedia

Revision as of 04:48, 7 October 2022

Potent and Selective Phosphodiesterase 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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