7W4X

Crystal structure of PDE4D catalytic domain complexed with 17

Summary for 7W4X

• Entry DOI: 10.2210/pdb7w4x/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: camp-specific 3', 5'-cyclic phosphodiesterase 4d, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 86414.35

Authors

Huang, Y.-Y.,Luo, H.-B. (deposition date: 2021-11-29, release date: 2022-03-16, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.20007326465 Å)