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The crystal structure of PDE4D with Pinoresinol Dimethyl Ether
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 PubMedPsoriasis is a complex chronic inflammatory disease that severely impairs patients' quality of life. However, current medications could only control the symptoms but not cure psoriasis with unmet medical needs. Targeting phosphodiesterase 4 (PDE4) represents a validated therapeutic strategy for psoriasis, though the clinical application of existing PDE4 inhibitors is often hampered by systemic side effects. In this study, we identified pinoresinol dimethyl ether (PDME), a natural furanoid lignan previously reported to be isolated from the stem bark of Magnolia Kobus, as a novel PDE4 inhibitor (IC(50) = 0.90 muM) through an integrated virtual screening approach. The binding mode of PDME to PDE4 was clearly elucidated through molecular dynamics simulations, isothermal titration calorimetry, and co-crystal structure analysis, revealing an enthalpy-driven interaction involving key hydrogen bonds with Gln369 and pi-pi stacking within the hydrophobic clamp. In vitro, PDME significantly suppressed the expression of pro-inflammatory cytokines in keratinocytes. In a murine imiquimod-induced psoriasis model, PDME treatment markedly alleviated psoriatic lesions, reduced skin thickening, and suppressed inflammatory responses. These findings highlight PDME as a promising natural PDE4 inhibitor with significant potential for the treatment of psoriasis. Discovery of pinoresinol dimethyl ether as a natural PDE4 inhibitor with anti-psoriatic effects.,Liu X, Gu W, Zhou Y, Wu L, Chen Z, Xiao K, Cao Y, Wu Q, Cao Z, Huang S, Li B, Huang YY, Luo HB Bioorg Chem. 2026 Feb;169:109414. doi: 10.1016/j.bioorg.2025.109414. Epub 2025 , Dec 22. PMID:41453305[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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