PDBsum entry 3w5e

Hydrolase/hydrolase inhibitor

PDB id: 3w5e

Contents

Protein chains

345 a.a.

Ligands

NVW ×2

Metals

_CA ×2

_ZN ×2

Waters ×340

PDB id:

3w5e

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of phosphodiesterase 4b in complex with compound 31e

Structure:

Camp-specific 3',5'-cyclic phosphodiesterase 4b. Chain: a, b. Fragment: unp residues 324-700. Synonym: dpde4, pde32. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dpde4, pde4b. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.30Å R-factor: 0.190 R-free: 0.269

Authors:

M.Takahashi,H.Hanzawa

Key ref:

T.Goto et al. (2013). Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors. Bioorg Med Chem Lett, 23, 3325-3328. PubMed id: 23602400 DOI: 10.1016/j.bmcl.2013.03.104

Date:

28-Jan-13 Release date: 29-May-13

Protein chains

Q07343  (PDE4B_HUMAN) -  3',5'-cyclic-AMP phosphodiesterase 4B from Homo sapiens

Seq: 736 a.a.

Struc: 345 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.4.53 - 3',5'-cyclic-AMP phosphodiesterase.
• Reaction: 3',5'-cyclic AMP + H2O = AMP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.bmcl.2013.03.104

Bioorg Med Chem Lett 23:3325-3328 (2013)

PubMed id: 23602400

Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.

T.Goto, A.Shiina, T.Yoshino, K.Mizukami, K.Hirahara, O.Suzuki, Y.Sogawa, T.Takahashi, T.Mikkaichi, N.Nakao, M.Takahashi, M.Hasegawa, S.Sasaki.

ABSTRACT

2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50=150nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50=25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50=7.5nM) and TNF-α production in mouse splenocytes (IC50=9.8nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50=18mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex.