PDBsum entry 5b4k

Hydrolase/hydrolase inhibitor

PDB id: 5b4k

Contents

Protein chains

315 a.a.

Ligands

6DT ×2

Metals

_MG ×2

_ZN ×2

Waters ×149

PDB id:

5b4k

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of the catalytic domain of human pde10a complexed with n-(4-((5-methyl-5h-pyrrolo[3,2-d]pyrimidin-4-yl)oxy)phenyl)-1h- benzimidazol-2-amine

Structure:

Camp and camp-inhibited cgmp 3',5'-cyclic phosphodiesterase 10a. Chain: a, b. Fragment: catalytic domain, unp residues 442-779. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde10a. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.90Å R-factor: 0.181 R-free: 0.261

Authors:

H.Oki,Y.Zama

Key ref:

M.Yoshikawa et al. (2016). Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket. Bioorg Med Chem Lett, 24, 3447-3455. PubMed id: 27301679 DOI: 10.1016/j.bmc.2016.05.049

Date:

05-Apr-16 Release date: 29-Jun-16

Protein chains

Q9Y233  (PDE10_HUMAN) -  cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A from Homo sapiens

Seq: 779 a.a.

Struc: 315 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.4.17 - 3',5'-cyclic-nucleotide phosphodiesterase.
• Reaction: a nucleoside 3',5'-cyclic phosphate + H2O = a nucleoside 5'-phosphate + H⁺

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

Added reference

DOI no: 10.1016/j.bmc.2016.05.049

Bioorg Med Chem Lett 24:3447-3455 (2016)

PubMed id: 27301679

Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket.

M.Yoshikawa, T.Hitaka, T.Hasui, M.Fushimi, J.Kunitomo, H.Kokubo, H.Oki, K.Nakashima, T.Taniguchi.

ABSTRACT

Utilizing structure-based drug design techniques, we designed and synthesized phosphodiesterase 10A (PDE10A) inhibitors based on pyridazin-4(1H)-one. These compounds can interact with Tyr683 in the PDE10A selectivity pocket. Pyridazin-4(1H)-one derivative 1 was linked with a benzimidazole group through an alkyl spacer to interact with the OH of Tyr683 and fill the PDE10A selectivity pocket. After optimizing the linker length, we identified 1-(cyclopropylmethyl)-5-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (16f) as having highly potent PDE10A inhibitory activity (IC50=0.76nM) and perfect selectivity against other PDEs (>13,000-fold, IC50=>10,000nM). The crystal structure of 16f bound to PDE10A revealed that the benzimidazole moiety was located deep within the PDE10A selectivity pocket and interacted with Tyr683. Additionally, a bidentate interaction existed between the 5-alkoxypyridazin-4(1H)-one moiety and the conserved Gln716 present in all PDEs.