PDBsum entry 4mvh

Hydrolase/hydrolase inhibitor

PDB id: 4mvh

Contents

Protein chains

307 a.a.

Ligands

SO4 ×12

2F5 ×2

Metals

_ZN ×4

Waters ×137

PDB id:

4mvh

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of pde10a with novel keto-benzimidazole inhibitor

Structure:

Camp and camp-inhibited cgmp 3',5'-cyclic phosphodiesterase 10a. Chain: a, b. Fragment: human pde10a, residues 442-779. Engineered: yes

Source:

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

Resolution:

2.50Å R-factor: 0.163 R-free: 0.182

Authors:

S.Chmait,S.Jordan

Key ref:

E.Hu et al. (2013). Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A). J Med Chem, 56, 8781-8792. PubMed id: 24102193 DOI: 10.1021/jm401234w

Date:

24-Sep-13 Release date: 23-Oct-13

Protein chains

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

Seq: 1055 a.a.

Struc: 307 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: 10.1021/jm401234w

J Med Chem 56:8781-8792 (2013)

PubMed id: 24102193

Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A).

E.Hu, R.K.Kunz, N.Chen, S.Rumfelt, A.Siegmund, K.Andrews, S.Chmait, S.Zhao, C.Davis, H.Chen, D.Lester-Zeiner, J.Ma, C.Biorn, J.Shi, A.Porter, J.Treanor, J.R.Allen.

ABSTRACT

Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.