9LRO

The crystal structure of PDE4D with T3700

This is a non-PDB format compatible entry.

Summary for 9LRO

• Entry DOI: 10.2210/pdb9lro/pdb
• Descriptor: 3',5'-cyclic-AMP phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: pde4 inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 78311.66

Authors

Huang, Y.-Y.,Luo, H.-B. (deposition date: 2025-02-01, release date: 2026-03-11)

Primary citation

Li, Z.,Huan, W.,Liu, X.,Zhang, K.,Wang, X.,Huang, Y.,Zhou, Q.,Huang, S.,Sang, Z.,Luo, H.B.
Artificial Intelligence-Driven Discovery of Pyrazolo[1,5- a ]pyrimidine Derivatives as Novel Phosphodiesterase 4 Inhibitors for Treating Idiopathic Pulmonary Fibrosis.
J.Med.Chem., 68:24436-24455, 2025

PubMed Abstract: Phosphodiesterase 4 (PDE4) has been validated as a promising therapeutic target for idiopathic pulmonary fibrosis (IPF), a devastating interstitial lung disease lacking really effective therapeutic drugs, particularly exacerbated in the post-COVID-19 era. Herein, we reported the discovery of , a novel pyrazolo[1,5-]pyrimidine-based PDE4 inhibitor, via an innovative artificial intelligence (AI)-driven virtual screening approach integrated with structure-based design. The cocrystal analysis of PDE4- elucidated the structural basis of its high affinity, revealing that the unique "halogen-binding and metal-coordination" synergistic network significantly influenced PDE4 inhibitory activity, which resulted in a 268-fold potency enhancement (IC = 2.7 nM) over hit (IC = 725 nM). Notably, exhibited remarkable hepatic microsomal stability (RLM = 141.4 min). Furthermore, exhibited remarkable antifibrotic activity in vitro and significantly attenuated bleomycin-induced pulmonary fibrosis in vivo, highlighting its potential as a novel PDE4 inhibitor for IPF.

PubMed: 41252469
DOI: 10.1021/acs.jmedchem.5c02407

Experimental method

X-RAY DIFFRACTION (2.2000069689 Å)