7CWG

Crystal structure of PDE8A catalytic domain in complex with 3a

Summary for 7CWG

• Entry DOI: 10.2210/pdb7cwg/pdb
• Descriptor: High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: camp-specific, hydrolase, selective pde8a inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 39534.48

Authors

Huang, Y.,Wu, X.-N.,Zhou, Q.,Wu, Y.,Luo, H.-B. (deposition date: 2020-08-28, release date: 2021-09-01, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.8 Å)