PDBsum entry 5c28

Hydrolase/hydrolase inhibitor

PDB id: 5c28

Contents

Protein chains

325 a.a.

Ligands

4XV

Metals

_MG ×2

_ZN ×2

Waters ×575

PDB id:

5c28

Name:

Hydrolase/hydrolase inhibitor

Title:

Pde10 complexed with 6-chloro-2-cyclopropyl-5-methyl-pyrimidin-4-amine

Structure:

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

Source:

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

Resolution:

1.56Å R-factor: 0.172 R-free: 0.196

Authors:

Y.Yan

Key ref:

W.D.Shipe et al. (2015). Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis. J Med Chem, 58, 7888-7894. PubMed id: 26378882 DOI: 10.1021/acs.jmedchem.5b00983

Date:

15-Jun-15 Release date: 30-Sep-15

Protein chains

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

Seq: 1055 a.a.

Struc: 325 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: 10.1021/acs.jmedchem.5b00983

J Med Chem 58:7888-7894 (2015)

PubMed id: 26378882

Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis.

W.D.Shipe, S.S.Sharik, J.C.Barrow, G.B.McGaughey, C.R.Theberge, J.M.Uslaner, Y.Yan, J.J.Renger, S.M.Smith, P.J.Coleman, C.D.Cox.

ABSTRACT

Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.