PDBsum entry 3ws8

Hydrolase/hydrolase inhibitor

PDB id: 3ws8

Contents

Protein chains

324 a.a.

Ligands

X4C ×2

Metals

_ZN ×2

_MG ×2

Waters ×19

PDB id:

3ws8

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of pde10a in complex with a benzimidazole inhibitor

Structure:

Camp and camp-inhibited cgmp 3',5'-cyclic phosphodiesterase 10a. Chain: a, b. Fragment: catalytic domain, unp residues 439-779. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde10a. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.60Å R-factor: 0.224 R-free: 0.314

Authors:

Y.Amano,K.Honbou

Key ref:

A.Chino et al. (2014). Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability. Bioorg Med Chem Lett, 22, 3515-3526. PubMed id: 24837154 DOI: 10.1016/j.bmc.2014.04.023

Date:

04-Mar-14 Release date: 04-Jun-14

Protein chains

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

Seq: 779 a.a.

Struc: 324 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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.2014.04.023

Bioorg Med Chem Lett 22:3515-3526 (2014)

PubMed id: 24837154

Novel benzimidazole derivatives as phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability.

A.Chino, N.Masuda, Y.Amano, K.Honbou, T.Mihara, M.Yamazaki, M.Tomishima.

ABSTRACT

In this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b. Following further structure-activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35, which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition.