3G3N

PDE7A catalytic domain in complex with 3-(2,6-difluorophenyl)-2-(methylthio)quinazolin-4(3H)-one

3G3N の概要

• エントリーDOI: 10.2210/pdb3g3n/pdb
• 分子名称: 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)
• 機能のキーワード: pde7, crystal, inhibitor complex, alternative splicing, camp, hydrolase, phosphoprotein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Isoform PDE7A1: Cytoplasm, cytosol. Isoform PDE7A2: Cytoplasm: Q13946
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37293.16

構造登録者

Castano, T.,Wang, H. (登録日: 2009-02-02, 公開日: 2009-04-28, 最終更新日: 2024-02-21)

主引用文献

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

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: 19350606
DOI: 10.1002/cmdc.200900043

実験手法

X-RAY DIFFRACTION (2.4 Å)