9wp3: Difference between revisions

Latest revision as of 07:26, 18 February 2026

The crystal structure of PDE2A complexed with inhibitor 13j

Structural highlights

9wp3 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5018392Å
Ligands:	A1E46, MG, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PDE2A_HUMAN Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.^[1] ^[2]

Publication Abstract from PubMed

Phosphodiesterase 2 (PDE2), a dual-substrate cyclic nucleotide hydrolase, represents a potential therapeutic target for cognitive impairment. This study aims to develop 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one-based PDE2 inhibitors with favorable drug-like properties for the treatment of Alzheimer's disease. Through scaffold hopping and cocrystal structure analysis, compound 14c was identified as an effective PDE2 inhibitor (IC(50) = 0.6 muM, aqueous solubility = 60.36 mug/mL). Moreover, 14c demonstrated favorable hepatic microsomal stability, pharmacokinetic properties (t(1/2) = 4.4 h, F% = 95.66 %) and promising safety both in vitro and in vivo. In the OKA-induced AD mice models, administration of 14c significantly improved memory deficits and cognitive impairment. Molecular mechanism studies revealed that the neuroprotective effects of 14c were mediated through the PKA/CREB/BDNF signaling pathway. Collectively, these findings represent significant advances in developing PDE2 inhibitors with favorable drug-like properties and establish a solid foundation for their therapeutic application in AD.

Discovery of novel 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one derivatives as PDE2 inhibitors with Alzheimer's disease therapeutic potential.,Yang F, Guo Q, Chen M, Wang W, Chen X, Zhang S, Bian H, Li J, Jiao Z, Wang Q, Xiong W, Huang YY, Liu Y, Xu C, Huang L Eur J Med Chem. 2026 Jan 15;302(Pt 1):118302. doi: 10.1016/j.ejmech.2025.118302. , Epub 2025 Oct 24. PMID:41151129^[3]

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

References

↑ Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T. Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system. Biochemistry. 2005 Jun 14;44(23):8312-25. PMID:15938621 doi:10.1021/bi047313h
↑ Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci U S A. 2009 Oct 14. PMID:19828435
↑ Yang F, Guo Q, Chen M, Wang W, Chen X, Zhang S, Bian H, Li J, Jiao Z, Wang Q, Xiong W, Huang YY, Liu Y, Xu C, Huang L. Discovery of novel 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one derivatives as PDE2 inhibitors with Alzheimer's disease therapeutic potential. Eur J Med Chem. 2026 Jan 15;302(Pt 1):118302. PMID:41151129 doi:10.1016/j.ejmech.2025.118302

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T. Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system. Biochemistry. 2005 Jun 14;44(23):8312-25. PMID:15938621 doi:10.1021/bi047313h

[2] Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci U S A. 2009 Oct 14. PMID:19828435

[3] Yang F, Guo Q, Chen M, Wang W, Chen X, Zhang S, Bian H, Li J, Jiao Z, Wang Q, Xiong W, Huang YY, Liu Y, Xu C, Huang L. Discovery of novel 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one derivatives as PDE2 inhibitors with Alzheimer's disease therapeutic potential. Eur J Med Chem. 2026 Jan 15;302(Pt 1):118302. PMID:41151129 doi:10.1016/j.ejmech.2025.118302

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9wp3 is ON HOLD
+==The crystal structure of PDE2A complexed with inhibitor 13j==
+<StructureSection load='9wp3' size='340' side='right'caption='[[9wp3]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9wp3]] is a 4 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=9WP3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9WP3 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]] 2.5018392&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1E46:7-oxidanylidene-~{N}-[(1~{S})-1-[4-(trifluoromethyl)phenyl]propyl]-2,4,5,6-tetrahydropyrazolo[3,4-c]pyridine-3-carboxamide'>A1E46</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=9wp3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9wp3 OCA], [https://pdbe.org/9wp3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9wp3 RCSB], [https://www.ebi.ac.uk/pdbsum/9wp3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9wp3 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/PDE2A_HUMAN PDE2A_HUMAN] Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.<ref>PMID:15938621</ref> <ref>PMID:19828435</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Phosphodiesterase 2 (PDE2), a dual-substrate cyclic nucleotide hydrolase, represents a potential therapeutic target for cognitive impairment. This study aims to develop 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one-based PDE2 inhibitors with favorable drug-like properties for the treatment of Alzheimer's disease. Through scaffold hopping and cocrystal structure analysis, compound 14c was identified as an effective PDE2 inhibitor (IC(50) = 0.6 muM, aqueous solubility = 60.36 mug/mL). Moreover, 14c demonstrated favorable hepatic microsomal stability, pharmacokinetic properties (t(1/2) = 4.4 h, F% = 95.66 %) and promising safety both in vitro and in vivo. In the OKA-induced AD mice models, administration of 14c significantly improved memory deficits and cognitive impairment. Molecular mechanism studies revealed that the neuroprotective effects of 14c were mediated through the PKA/CREB/BDNF signaling pathway. Collectively, these findings represent significant advances in developing PDE2 inhibitors with favorable drug-like properties and establish a solid foundation for their therapeutic application in AD.
-Authors: Huang, Y.-Y., Luo, H.-B.
+Discovery of novel 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one derivatives as PDE2 inhibitors with Alzheimer's disease therapeutic potential.,Yang F, Guo Q, Chen M, Wang W, Chen X, Zhang S, Bian H, Li J, Jiao Z, Wang Q, Xiong W, Huang YY, Liu Y, Xu C, Huang L Eur J Med Chem. 2026 Jan 15;302(Pt 1):118302. doi: 10.1016/j.ejmech.2025.118302. , Epub 2025 Oct 24. PMID:41151129<ref>PMID:41151129</ref>
-Description: The crystal structure of PDE2A complexed with inhibitor 13j
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Luo, H.-B]]
+<div class="pdbe-citations 9wp3" style="background-color:#fffaf0;"></div>
-[[Category: Huang, Y.-Y]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Huang Y-Y]]
+[[Category: Luo H-B]]

9wp3: Difference between revisions

Latest revision as of 07:26, 18 February 2026

The crystal structure of PDE2A complexed with inhibitor 13j

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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