3wd9: Difference between revisions
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== | ==Crystal structure of phosphodiesterase 4B in complex with compound 10f== | ||
[[http://www.uniprot.org/uniprot/PDE4B_HUMAN PDE4B_HUMAN | <StructureSection load='3wd9' size='340' side='right'caption='[[3wd9]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3wd9]] 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=3WD9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WD9 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=QPC:4-[(4-{2-[(2,2-DIMETHYLPROPYL)AMINO]-2-OXOETHYL}PHENYL)AMINO]-2-PHENYLPYRIMIDINE-5-CARBOXAMIDE'>QPC</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=3wd9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wd9 OCA], [https://pdbe.org/3wd9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wd9 RCSB], [https://www.ebi.ac.uk/pdbsum/3wd9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wd9 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PDE4B_HUMAN PDE4B_HUMAN] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.<ref>PMID:10846163</ref> <ref>PMID:15003452</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-alpha) production in mouse splenocytes (IC50=0.21nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0mg/kg, i.t.). | |||
Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.,Goto T, Shiina A, Yoshino T, Mizukami K, Hirahara K, Suzuki O, Sogawa Y, Takahashi T, Mikkaichi T, Nakao N, Takahashi M, Hasegawa M, Sasaki S Bioorg Med Chem. 2013 Nov 15;21(22):7025-37. doi: 10.1016/j.bmc.2013.09.013. Epub, 2013 Sep 19. PMID:24094436<ref>PMID:24094436</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
< | </div> | ||
[[ | <div class="pdbe-citations 3wd9" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Hanzawa H]] | ||
[[Category: | [[Category: Takahashi M]] | ||
Latest revision as of 16:05, 8 November 2023
Crystal structure of phosphodiesterase 4B in complex with compound 10fCrystal structure of phosphodiesterase 4B in complex with compound 10f
Structural highlights
FunctionPDE4B_HUMAN Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.[1] [2] Publication Abstract from PubMed5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-alpha) production in mouse splenocytes (IC50=0.21nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0mg/kg, i.t.). Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.,Goto T, Shiina A, Yoshino T, Mizukami K, Hirahara K, Suzuki O, Sogawa Y, Takahashi T, Mikkaichi T, Nakao N, Takahashi M, Hasegawa M, Sasaki S Bioorg Med Chem. 2013 Nov 15;21(22):7025-37. doi: 10.1016/j.bmc.2013.09.013. Epub, 2013 Sep 19. PMID:24094436[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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