6KK0

Crystal structure of PDE4D catalytic domain complexed with compound 4e

Summary for 6KK0

• Entry DOI: 10.2210/pdb6kk0/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, 7-[8-methoxy-2,2-dimethyl-7-(3-methylbut-2-enyl)-5-oxidanyl-6-oxidanylidene-pyrano[3,2-b]xanthen-9-yl]oxyheptanoic acid, ZINC ION, ... (5 entities in total)
• Functional Keywords: pde4 inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 76409.84

Authors

Huang, Y.-Y.,He, X.,Luo, H.-B. (deposition date: 2019-07-23, release date: 2020-03-18, Last modification date: 2023-11-22)

Primary citation

Liang, J.,Huang, Y.Y.,Zhou, Q.,Gao, Y.,Li, Z.,Wu, D.,Yu, S.,Guo, L.,Chen, Z.,Huang, L.,Liang, S.H.,He, X.,Wu, R.,Luo, H.B.
Discovery and Optimization of alpha-Mangostin Derivatives as Novel PDE4 Inhibitors for the Treatment of Vascular Dementia.
J.Med.Chem., 63:3370-3380, 2020

PubMed Abstract: To validate PDE4 inhibitors as novel therapeutic agents against vascular dementia (VaD), 25 derivatives were discovered from the natural inhibitor α-mangostin (IC = 1.31 μM). Hit-to-lead optimization identified a novel and selective PDE4 inhibitor (IC = 17 nM), which adopted a different binding pattern from PDE4 inhibitors roflumilast and rolipram. Oral administration of at a dose of 10 mg/kg exhibited remarkable therapeutic effects in a VaD model and did not cause emesis to beagle dogs, indicating its potential as a novel anti-VaD agent.

PubMed: 32115956
DOI: 10.1021/acs.jmedchem.0c00060

Experimental method

X-RAY DIFFRACTION (2.20008760676 Å)