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==Crystal structure of PDE10A in complex with a benzimidazole inhibitor== | ==Crystal structure of PDE10A in complex with a benzimidazole inhibitor== | ||
<StructureSection load='3ws8' size='340' side='right'caption='[[3ws8]]' scene=''> | <StructureSection load='3ws8' size='340' side='right'caption='[[3ws8]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WS8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WS8 FirstGlance]. <br> | <table><tr><td colspan='2'>[[3ws8]] 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=3WS8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WS8 FirstGlance]. <br> | ||
</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=3ws8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ws8 OCA], [https://pdbe.org/3ws8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ws8 RCSB], [https://www.ebi.ac.uk/pdbsum/3ws8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ws8 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=X4C:8-METHYL-6-[2-(5-METHYL-1-PHENYL-1H-BENZIMIDAZOL-2-YL)ETHYL]IMIDAZO[1,5-A]PYRIMIDINE'>X4C</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=3ws8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ws8 OCA], [https://pdbe.org/3ws8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ws8 RCSB], [https://www.ebi.ac.uk/pdbsum/3ws8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ws8 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[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 == | |||
In this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b. Following further structure-activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35, which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition. | |||
Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability.,Chino A, Masuda N, Amano Y, Honbou K, Mihara T, Yamazaki M, Tomishima M Bioorg Med Chem. 2014 Jul 1;22(13):3515-26. doi: 10.1016/j.bmc.2014.04.023. Epub , 2014 Apr 20. PMID:24837154<ref>PMID:24837154</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3ws8" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] | *[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Amano Y]] | [[Category: Amano Y]] | ||
[[Category: Honbou K]] | [[Category: Honbou K]] | ||
Latest revision as of 16:25, 8 November 2023
Crystal structure of PDE10A in complex with a benzimidazole inhibitorCrystal structure of PDE10A in complex with a benzimidazole inhibitor
Structural highlights
FunctionPDE10_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 PubMedIn this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b. Following further structure-activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35, which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition. Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability.,Chino A, Masuda N, Amano Y, Honbou K, Mihara T, Yamazaki M, Tomishima M Bioorg Med Chem. 2014 Jul 1;22(13):3515-26. doi: 10.1016/j.bmc.2014.04.023. Epub , 2014 Apr 20. PMID:24837154[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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