View source for 9lro


==The crystal structure of PDE4D with T3700==
<StructureSection load='9lro' size='340' side='right'caption='[[9lro]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9lro]] 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=9LRO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9LRO 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]] 2.200007&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1ELI:6-bromanyl-3-(1-methylpyrazol-4-yl)-5-[(3~{S})-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine'>A1ELI</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=9lro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9lro OCA], [https://pdbe.org/9lro PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9lro RCSB], [https://www.ebi.ac.uk/pdbsum/9lro PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9lro ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PDE4D_HUMAN PDE4D_HUMAN] Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution.  Defects in PDE4D are the cause of acrodysostosis type 2, with or without hormone resistance (ACRDYS2) [MIM:[https://omim.org/entry/614613 614613]. ACRDYS2 is a pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems.<ref>PMID:22464250</ref> 
== Function ==
[https://www.uniprot.org/uniprot/PDE4D_HUMAN PDE4D_HUMAN] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.<ref>PMID:15260978</ref> <ref>PMID:15576036</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Phosphodiesterase 4 (PDE4) has been validated as a promising therapeutic target for idiopathic pulmonary fibrosis (IPF), a devastating interstitial lung disease lacking really effective therapeutic drugs, particularly exacerbated in the post-COVID-19 era. Herein, we reported the discovery of 13c, a novel pyrazolo[1,5-a]pyrimidine-based PDE4 inhibitor, via an innovative artificial intelligence (AI)-driven virtual screening approach integrated with structure-based design. The cocrystal analysis of PDE4-13c elucidated the structural basis of its high affinity, revealing that the unique "halogen-binding and metal-coordination" synergistic network significantly influenced PDE4 inhibitory activity, which resulted in a 268-fold potency enhancement (IC(50) = 2.7 nM) over hit T3700 (IC(50) = 725 nM). Notably, 13c exhibited remarkable hepatic microsomal stability (RLM(1/2) = 141.4 min). Furthermore, 13c exhibited remarkable antifibrotic activity in vitro and significantly attenuated bleomycin-induced pulmonary fibrosis in vivo, highlighting its potential as a novel PDE4 inhibitor for IPF.

Artificial Intelligence-Driven Discovery of Pyrazolo[1,5-a]pyrimidine Derivatives as Novel Phosphodiesterase 4 Inhibitors for Treating Idiopathic Pulmonary Fibrosis.,Li Z, Huan W, Liu X, Zhang K, Wang X, Huang Y, Zhou Q, Huang S, Sang Z, Luo HB J Med Chem. 2025 Nov 27;68(22):24436-24455. doi: 10.1021/acs.jmedchem.5c02407. , Epub 2025 Nov 18. PMID:41252469<ref>PMID:41252469</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9lro" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Huang Y-Y]]
[[Category: Luo H-B]]