5K1I

PDE4 crystal structure in complex with small molecule inhibitor

Summary for 5K1I

• Entry DOI: 10.2210/pdb5k1i/pdb
• Descriptor: cAMP-specific 3',5'-cyclic phosphodiesterase 4D, 4-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]benzoic acid, ZINC ION, ... (5 entities in total)
• Functional Keywords: phosphodiesterases, inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Apical cell membrane : Q08499
• Total number of polymer chains: 8
• Total formula weight: 304365.61

Authors

Segarra, V.,Hernandez, B.,Ferrer-Miralles, N.,Korndoerfer, I.,Aymami, J. (deposition date: 2016-05-18, release date: 2016-12-21, Last modification date: 2024-01-10)

Primary citation

Gracia, J.,Buil, M.A.,Castro, J.,Eichhorn, P.,Ferrer, M.,Gavalda, A.,Hernandez, B.,Segarra, V.,Lehner, M.D.,Moreno, I.,Pages, L.,Roberts, R.S.,Serrat, J.,Sevilla, S.,Taltavull, J.,Andres, M.,Cabedo, J.,Vilella, D.,Calama, E.,Carcasona, C.,Miralpeix, M.
Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure-Activity Relationships.
J. Med. Chem., 59:10479-10497, 2016

PubMed Abstract: Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer.

PubMed: 27933955
DOI: 10.1021/acs.jmedchem.6b00829

Experimental method

X-RAY DIFFRACTION (2.61 Å)