9lrp
The crystal structure of PDE4D with 13c
Structural highlights
DiseasePDE4D_HUMAN Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. Defects in PDE4D are the cause of acrodysostosis type 2, with or without hormone resistance (ACRDYS2) [MIM:614613. ACRDYS2 is a pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems.[1] FunctionPDE4D_HUMAN Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.[2] [3] Publication Abstract from PubMedPhosphodiesterase 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 13c, a novel pyrazolo[1,5-a]pyrimidine-based PDE4 inhibitor, via an innovative artificial intelligence (AI)-driven virtual screening approach integrated with structure-based design. The cocrystal analysis of PDE4-13c 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(50) = 2.7 nM) over hit T3700 (IC(50) = 725 nM). Notably, 13c exhibited remarkable hepatic microsomal stability (RLM(1/2) = 141.4 min). Furthermore, 13c 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. Artificial Intelligence-Driven Discovery of Pyrazolo[1,5-a]pyrimidine Derivatives as Novel Phosphodiesterase 4 Inhibitors for Treating Idiopathic Pulmonary Fibrosis.,Li Z, Huan W, Liu X, Zhang K, Wang X, Huang Y, Zhou Q, Huang S, Sang Z, Luo HB J Med Chem. 2025 Nov 27;68(22):24436-24455. doi: 10.1021/acs.jmedchem.5c02407. , Epub 2025 Nov 18. PMID:41252469[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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