PDBsum entry 6cyb

Hydrolase/hydrolase inhibitor

PDB id: 6cyb

Contents

Protein chains

343 a.a.

Ligands

EDO ×8

FKV ×2

Metals

_ZN ×2

_MG ×2

Waters ×369

PDB id:

6cyb

Name:

Hydrolase/hydrolase inhibitor

Title:

Pde2 in complex with compound 7

Structure:

Cgmp-dependent 3',5'-cyclic phosphodiesterase. Chain: a, b. Synonym: cyclic gmp-stimulated phosphodiesterase,cgspde. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde2a. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.62Å R-factor: 0.180 R-free: 0.201

Authors:

J.Lu

Key ref:

S.J.Stachel et al. (2018). Structure-Guided Design and Procognitive Assessment of a Potent and Selective Phosphodiesterase 2A Inhibitor. ACS Med Chem Lett, 9, 815-820. PubMed id: 30128073

Date:

05-Apr-18 Release date: 19-Sep-18

Protein chains

O00408  (PDE2A_HUMAN) -  cGMP-dependent 3',5'-cyclic phosphodiesterase from Homo sapiens

Seq: 941 a.a.

Struc: 343 a.a.*

* PDB and UniProt seqs differ at 8 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

ACS Med Chem Lett 9:815-820 (2018)

PubMed id: 30128073

Structure-Guided Design and Procognitive Assessment of a Potent and Selective Phosphodiesterase 2A Inhibitor.

S.J.Stachel, R.Berger, A.B.Nomland, A.T.Ginnetti, D.V.Paone, D.Wang, V.Puri, H.Lange, J.Drott, J.Lu, J.Marcus, M.P.Dwyer, S.Suon, J.M.Uslaner, S.M.Smith.

ABSTRACT

Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound 3, while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound 3 was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography. An optimized lead, 4, demonstrated improved performance in both a rodent and a nonhuman primate cognition model.