9VDD

The crystal structure of PDE4D with inhibitor LH17

This is a non-PDB format compatible entry.

Summary for 9VDD

• Entry DOI: 10.2210/pdb9vdd/pdb
• Descriptor: 3',5'-cyclic-AMP 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: 76535.88

Authors

Huang, Y.-Y.,Luo, H.-B. (deposition date: 2025-06-08, release date: 2026-05-06)

Primary citation

Cao, Y.,Liao, X.,Huang, P.,Lu, R.,Wu, Q.,Zhong, K.,Wang, X.,Yang, Y.,Liu, X.,Fan, J.J.,Chen, F.,Wang, X.,He, X.,Luo, H.B.
Discovery of kaempferol derivatives as novel PDE4 inhibitors for treatment of idiopathic pulmonary fibrosis.
Eur.J.Med.Chem., 304:118505-118505, 2026

PubMed Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with a rapidly rising global incidence. Despite its growing prevalence, effective therapeutic options for IPF remain limited. Phosphodiesterase 4 (PDE4) inhibitors have recently emerged as promising anti-fibrotic candidates. In this study, the natural product kaempferol was identified as a weak PDE4 inhibitor with half maximal inhibitory concentration (IC) of 22 μM and structure-based optimization by targeting M-pocket was performed, yielding a lead compound LH17 with dramatically improved potency (IC of 73 nM). Crystallographic analysis revealed that this kaempferol-derived compound LH17 displayed distinct interactions with PDE4 M-pocket. Notably, lead LH17 demonstrated remarkable anti-fibrotic efficacy in both in vitro and in vivo models, underscoring its potential as a novel therapeutic agent for IPF treatment. This study also could establish a rational strategy for optimizing weakly bioactive natural PDE4 inhibitors into potent therapeutics.

PubMed: 41443085
DOI: 10.1016/j.ejmech.2025.118505

Experimental method

X-RAY DIFFRACTION (2.3 Å)