5K32

PDE4D crystal structure in complex with small molecule inhibitor

Summary for 5K32

• Entry DOI: 10.2210/pdb5k32/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, ZINC ION, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: phosphodiesterases, inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Apical cell membrane : Q08499
• Total number of polymer chains: 2
• Total formula weight: 77695.30

Authors

Segarra, V.,Hernandez, B.,Roberts, R.,Gracia, J.,Soler, M.,Bonin, I.,Aymami, J. (deposition date: 2016-05-19, release date: 2017-03-29, Last modification date: 2024-01-10)

Primary citation

Roberts, R.S.,Sevilla, S.,Ferrer, M.,Taltavull, J.,Hernandez, B.,Segarra, V.,Gracia, J.,Lehner, M.D.,Gavalda, A.,Andres, M.,Cabedo, J.,Vilella, D.,Eichhorn, P.,Calama, E.,Carcasona, C.,Miralpeix, M.
4-Amino-7,8-dihydro-1,6-naphthyridin-5(6 H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure-Activity Relationships.
J. Med. Chem., 61:2472-2489, 2018

PubMed Abstract: Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.

PubMed: 29502405
DOI: 10.1021/acs.jmedchem.7b01751

Experimental method

X-RAY DIFFRACTION (1.99 Å)