7XAA

Crystal structure of PDE4D catalytic domain complexed with compound 21d

Summary for 7XAA

• Entry DOI: 10.2210/pdb7xaa/pdb
• Descriptor: Isoform 3 of cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: pde4 inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 116897.54

Authors

Huang, Y.-Y.,He, X.,Luo, H.-B. (deposition date: 2022-03-17, release date: 2023-02-22, Last modification date: 2023-11-29)

Primary citation

Liu, H.,Wang, Q.,Huang, Y.,Deng, J.,Xie, X.,Zhu, J.,Yuan, Y.,He, Y.M.,Huang, Y.Y.,Luo, H.B.,He, X.
Discovery of novel PDE4 inhibitors targeting the M-pocket from natural mangostanin with improved safety for the treatment of Inflammatory Bowel Diseases.
Eur.J.Med.Chem., 242:114631-114631, 2022

PubMed Abstract: Inflammatory Bowel Diseases (IBDs) are chronic disorders with iterative intestinal mucosal inflammation which remain unmet medical needs. PDE4 inhibitors were reported to be novel anti-IBD agents, but their clinical use was hampered by side effects such as emesis and nausea. Herein, structure-based discovery of natural mangostanin (1) targeting the M-pocket resulted in the novel and potent PDE4 inhibitor 22d (IC = 3.5 nM) and favorable physico-chemical properties. X-Ray study revealed that 22d interacted tightly with the M-pocket and maintained the key interactions between PDE4 and roflumilast. Worthy to note that compounds 22d and our previously reported 4e and 18a, originating from mangostanin, all caused no emesis on beagle dogs at the oral dose of 10 mg/kg, confirming the safety superiority of scaffold in mangostanin derivatives over that in positive roflumilast. Finally, administration of 22d (5.0 mg/kg, twice-daily) exhibited comparable anti-IBD effects to the positive control dipyridamole (25.0 mg/kg, twice-daily) in the dextran sulfate sodium (DSS)-induced IBD mice model, indicating its potential as a novel anti-IBD agent.

PubMed: 35985255
DOI: 10.1016/j.ejmech.2022.114631

Experimental method

X-RAY DIFFRACTION (2.10041402486 Å)