7W4X

Crystal structure of PDE4D catalytic domain complexed with 17

7W4X の概要

• エントリーDOI: 10.2210/pdb7w4x/pdb
• 分子名称: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: camp-specific 3', 5'-cyclic phosphodiesterase 4d, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 86414.35

構造登録者

Huang, Y.-Y.,Luo, H.-B. (登録日: 2021-11-29, 公開日: 2022-03-16, 最終更新日: 2023-11-29)

主引用文献

Song, Z.,Huang, Y.Y.,Hou, K.Q.,Liu, L.,Zhou, F.,Huang, Y.,Wan, G.,Luo, H.B.,Xiong, X.F.
Discovery and Structural Optimization of Toddacoumalone Derivatives as Novel PDE4 Inhibitors for the Topical Treatment of Psoriasis.
J.Med.Chem., 65:4238-4254, 2022

PubMed Abstract: Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and phosphodiesterase 4 (PDE4) is an effective target for the treatment of inflammatory diseases such as psoriasis. Toddacoumalone is a natural PDE4 inhibitor with moderate potency and imperfect drug-like properties. To discover novel and potent PDE4 inhibitors with considerable druggability, a series of toddacoumalone derivatives were designed and synthesized, leading to the compound (2,4)-6-ethyl-2-(2-hydroxyethyl)-2,8-dimethyl-4-(2-methylprop-1-en-1-yl)-2,3,4,6-tetrahydro-5-pyrano[3,2-][1,8]naphthyridin-5-one () with high inhibitory potency (IC = 3.1 nM), satisfactory selectivity, favorable skin permeability, and a well-characterized binding mechanism. Encouragingly, topical administration of exhibited remarkable therapeutic effects in an imiquimod-induced psoriasis mouse model.

PubMed: 35188767
DOI: 10.1021/acs.jmedchem.1c02058

実験手法

X-RAY DIFFRACTION (2.20007326465 Å)