PDBsum entry 3hr1

Hydrolase/hydrolase inhibitor

PDB id

3hr1

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Contents

			Protein chain

					305 a.a. *

			Ligands

					SO4-SO4


					PF9

			Metals

					_MG


					_ZN

			Waters ×456

* Residue conservation analysis

PDB id:

3hr1

Links

Name:

Hydrolase/hydrolase inhibitor

Title:

Discovery of novel inhibitors of pde10a

Structure:

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

Source:

Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: pde10a. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

1.53Å

R-factor:

0.186

R-free:

0.211

Authors:

J.Pandit,E.S.Marr

Key ref:

P.R.Verhoest et al. (2009). Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia. J Med Chem, 52, 5188-5196. PubMed id: 19630403

Date:

08-Jun-09

Release date:

04-Aug-09

PROCHECK

	Headers

	References

Protein chain

Q9QYJ6 (PDE10_RAT) - cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A from Rattus norvegicus

Seq: Struc:

Seq: Struc:					794 a.a. 305 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.3.1.4.17 - 3',5'-cyclic-nucleotide phosphodiesterase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

a nucleoside 3',5'-cyclic phosphate + H2O = a nucleoside 5'-phosphate + H⁺

nucleoside 3',5'-cyclic phosphate	+	H2O	=	nucleoside 5'-phosphate	+	H(+)

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

Added reference

	J Med Chem 52:5188-5196 (2009)
PubMed id: 19630403

Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia.
P.R.Verhoest, D.S.Chapin, M.Corman, K.Fonseca, J.F.Harms, X.Hou, E.S.Marr, F.S.Menniti, F.Nelson, R.O'Connor, J.Pandit, C.Proulx-Lafrance, A.W.Schmidt, C.J.Schmidt, J.A.Suiciak, S.Liras.

ABSTRACT

By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20345171

C.Bissantz, B.Kuhn, and M.Stahl (2010).
A medicinal chemist's guide to molecular interactions.

J Med Chem, 53, 5061-5084.

20967473

C.Rundfeldt, K.Socała, and P.Wlaź (2010).
The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis.

J Neural Transm, 117, 1319-1325.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.