4D08

PDE2a catalytic domain in complex with a brain penetrant inhibitor

Summary for 4D08

• Entry DOI: 10.2210/pdb4d08/pdb
• Related: 4D09
• Descriptor: CGMP-DEPENDENT 3', 5'-CYCLIC PHOSPHODIESTERASE, ZINC ION, 1-(5-butoxypyridin-3-yl)-4-methyl-8-(morpholin-4-ylmethyl)[1,2,4]triazolo[4,3-a]quinoxaline, ... (5 entities in total)
• Functional Keywords: hydrolase, binding sites, catalytic domain, cyclic nucleotide phosphodiesterases, type 2, type 4, disease models, animal, drug evaluation, preclinical, phosphodiesterase 2 inhibitors, phosphodiesterase inhibitors, protein binding, structure-activity relationship
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Isoform PDE2A3: Cell membrane; Lipid-anchor. Isoform PDE2A2: Mitochondrion matrix. Isoform PDE2A1: Cytoplasm. Isoform 5: Mitochondrion (Probable): O00408
• Total number of polymer chains: 4
• Total formula weight: 167818.43

Authors

Buijnsters, P.,Andres, J.I.,DeAngelis, M.,Langlois, X.,Rombouts, F.,Sanderson, W.,Tresadern, G.,Trabanco, A.,VanHoof, G.,VanRoosbroeck, Y. (deposition date: 2014-04-24, release date: 2014-08-06, Last modification date: 2024-05-01)

Primary citation

Buijnsters, P.,De Angelis, M.,Langlois, X.,Rombouts, F.J.R.,Sanderson, W.,Tresadern, G.,Ritchie, A.,Trabanco, A.A.,Vanhoof, G.,Roosbroeck, Y.V.,Andres, J.
Structure-Based Design of a Potent, Selective, and Brain Penetrating Pde2 Inhibitor with Demonstrated Target Engagement.
Acs Med.Chem.Lett., 5:1049-, 2014

PubMed Abstract: Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up to 10 μM. In vivo evaluation of 12 provided evidence that it is able to engage the target and to increase cGMP levels in relevant brain regions. Hence, 12 is a valuable tool compound for the better understanding of the role of PDE2 in cognitive impairment and other central nervous system related disorders.

PubMed: 25221665
DOI: 10.1021/ML500262U

Experimental method

X-RAY DIFFRACTION (1.9 Å)