3G3N
PDE7A catalytic domain in complex with 3-(2,6-difluorophenyl)-2-(methylthio)quinazolin-4(3H)-one
Summary for 3G3N
| Entry DOI | 10.2210/pdb3g3n/pdb |
| Descriptor | High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A, 3-(2,6-difluorophenyl)-2-(methylthio)quinazolin-4(3H)-one, ZINC ION, ... (4 entities in total) |
| Functional Keywords | pde7, crystal, inhibitor complex, alternative splicing, camp, hydrolase, phosphoprotein |
| Biological source | Homo sapiens (human) |
| Cellular location | Isoform PDE7A1: Cytoplasm, cytosol. Isoform PDE7A2: Cytoplasm: Q13946 |
| Total number of polymer chains | 1 |
| Total formula weight | 37293.16 |
| Authors | Castano, T.,Wang, H. (deposition date: 2009-02-02, release date: 2009-04-28, Last modification date: 2024-02-21) |
| Primary citation | Castano, T.,Wang, H.,Campillo, N.E.,Ballester, S.,Gonzalez-Garcia, C.,Hernandez, J.,Perez, C.,Cuenca, J.,Perez-Castillo, A.,Martinez, A.,Huertas, O.,Gelpi, J.L.,Luque, F.J.,Ke, H.,Gil, C. Synthesis, structural analysis, and biological evaluation of thioxoquinazoline derivatives as phosphodiesterase 7 inhibitors Chemmedchem, 4:866-876, 2009 Cited by PubMed Abstract: PDE7 inhibitors regulate pro-inflammatory and immune T-cell functions, and are a potentially novel class of drugs especially useful in the treatment of a wide variety of immune and inflammatory disorders. Starting from our lead family of thioxoquinazolines, we designed, synthesized, and characterized a novel series of thioxoquinazoline derivatives. Many of these compounds showed inhibitory potencies at sub-micromolar levels against the catalytic domain of PDE7A1 and at the micromolar level against PDE4D2. Cell-based studies showed that these compounds not only increased intracellular cAMP levels, but also had interesting anti-inflammatory properties within a therapeutic window. The in silico data predict that these compounds are capable of the crossing the blood-brain barrier. The X-ray crystal structure of the PDE7A1 catalytic domain in complex with compound 15 at a resolution of 2.4 A demonstrated that hydrophobic interactions at the active site pocket are a key feature. This structure, together with molecular modeling, provides insight into the selectivity of the PDE inhibitors and a template for the discovery of new PDE7 or PDE7/PDE4 dual inhibitors. PubMed: 19350606DOI: 10.1002/cmdc.200900043 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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