7XBB

Crystal structure of PDE4D catalytic domain complexed with compound 23a

Summary for 7XBB

• Entry DOI: 10.2210/pdb7xbb/pdb
• Descriptor: Isoform 3 of cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: pde4 inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 116637.35

Authors

Huang, Y.-Y.,Luo, H.-B. (deposition date: 2022-03-21, release date: 2022-07-06, Last modification date: 2023-11-29)

Primary citation

Zhou, F.,Huang, Y.,Liu, L.,Song, Z.,Hou, K.Q.,Yang, Y.,Luo, H.B.,Huang, Y.Y.,Xiong, X.F.
Structure-based optimization of Toddacoumalone as highly potent and selective PDE4 inhibitors with anti-inflammatory effects.
Biochem Pharmacol, 202:115123-115123, 2022

PubMed Abstract: Phosphodiesterase-4 (PDE4) is an important drug target for inflammatory diseases. Previously, we identified a series of novel PDE4 inhibitors derived from the natural Toddacoumalone, among which the hit compound 2 with a naphthyridine scaffold showed moderate potency with the IC value of 400 nM. Based on the co-crystal structure of PDE4D-2, further structural optimizations and structure-activity relationship studies led to a highly potent PDE4 inhibitor 23a with the IC value of 0.25 nM and excellent selectivity profiles over other PDEs (>4000-fold). The co-crystal structure of PDE4D-23a elucidated that 23a has strong interactions with the M and Q pocket of PDE4D. Importantly, compound 23a significantly inhibits the release of inflammatory cytokines TNF-α and IL-6 in lipopolysaccharide-stimulated RAW264.7 cells. Thus, compound 23a with a naphthyridine scaffold is a promising PDE4 inhibitor for the treatment of inflammatory diseases.

PubMed: 35688178
DOI: 10.1016/j.bcp.2022.115123

Experimental method

X-RAY DIFFRACTION (2.10000900931 Å)