7CWA

Crystal structure of PDE8A catalytic domain in complex with clofarabine

7CWA の概要

• エントリーDOI: 10.2210/pdb7cwa/pdb
• 分子名称: High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: pde8a inhibitor, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39483.41

構造登録者

Huang, Y.,Wu, X.-N.,Zhou, Q.,Wu, Y.,Luo, H.-B. (登録日: 2020-08-27, 公開日: 2021-09-01, 最終更新日: 2024-11-06)

主引用文献

Huang, Y.,Wu, X.N.,Zhou, Q.,Wu, Y.,Zheng, D.,Li, Z.,Guo, L.,Luo, H.B.
Rational Design of 2-Chloroadenine Derivatives as Highly Selective Phosphodiesterase 8A Inhibitors.
J.Med.Chem., 63:15852-15863, 2020

PubMed Abstract: To validate the hypothesis that Tyr748 is a crucial residue to aid the discovery of highly selective phosphodiesterase 8A (PDE8A) inhibitors, we identified a series of 2-chloroadenine derivatives based on the hit clofarabine. Structure-based design targeting Tyr748 in PDE8 resulted in the lead compound (IC = 0.010 μM) with high selectivity with a reasonable druglike profile. In the X-ray crystal structure, bound to PDE8A with a different mode from 3-isobutyl-1-methylxanthine (a pan-PDE inhibitor) and gave a H-bond of 2.7 Å with Tyr748, which possibly interprets the 220-fold selectivity of against PDE2A. Additionally, oral administration of compound achieved remarkable therapeutic effects against vascular dementia (VaD), indicating that PDE8 inhibitors could serve as potential anti-VaD agents.

PubMed: 33291877
DOI: 10.1021/acs.jmedchem.0c01573

実験手法

X-RAY DIFFRACTION (2.8 Å)