PDBsum entry 6acb

Hydrolase/hydrolase inhibitor

PDB id: 6acb

Contents

Protein chain

308 a.a.

Ligands

SO4

9T9

Metals

_ZN

_MG

Waters ×45

PDB id:

6acb

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of pde5 in complex with inhibitor lw1805

Structure:

Cgmp-specific 3',5'-cyclic phosphodiesterase. Chain: a. Synonym: cgmp-binding cgmp-specific phosphodiesterase,cgb-pde. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pde5a, pde5. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Resolution:

2.80Å R-factor: 0.201 R-free: 0.268

Authors:

D.Wu,Y.D.Huang,Y.Y.Huang,H.B.Luo

Key ref:

D.Wu et al. (2018). Optimization of Chromeno[2,3- c]pyrrol-9(2 H)-ones as Highly Potent, Selective, and Orally Bioavailable PDE5 Inhibitors: Structure-Activity Relationship, X-ray Crystal Structure, and Pharmacodynamic Effect on Pulmonary Arterial Hypertension. J Med Chem, 61, 8468-8473. PubMed id: 30148362 DOI: 10.1021/acs.jmedchem.8b01209

Date:

26-Jul-18 Release date: 19-Sep-18

Protein chain

O76074  (PDE5A_HUMAN) -  cGMP-specific 3',5'-cyclic phosphodiesterase from Homo sapiens

Seq: 875 a.a.

Struc: 308 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.4.35 - 3',5'-cyclic-GMP phosphodiesterase.
• Reaction: 3',5'-cyclic GMP + H2O = GMP + H⁺

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

Added reference

DOI no: 10.1021/acs.jmedchem.8b01209

J Med Chem 61:8468-8473 (2018)

PubMed id: 30148362

Optimization of Chromeno[2,3- c]pyrrol-9(2 H)-ones as Highly Potent, Selective, and Orally Bioavailable PDE5 Inhibitors: Structure-Activity Relationship, X-ray Crystal Structure, and Pharmacodynamic Effect on Pulmonary Arterial Hypertension.

D.Wu, Y.Huang, Y.Chen, Y.Y.Huang, H.Geng, T.Zhang, C.Zhang, Z.Li, L.Guo, J.Chen, H.B.Luo.

ABSTRACT

To further explore the structure-activity relationship around the chromeno[2,3- c]pyrrol-9(2 H)-one scaffold, 19 derivatives as inhibitors against PDE5 were discovered. The most potent inhibitor 3 has an IC₅₀ of 0.32 nM with remarkable selectivity and druglike profile. Oral administration of 3 (1.25 mg/kg) caused comparable therapeutic effects to sildenafil (10.0 mg/kg) against pulmonary arterial hypertension. Further, different binding patterns from sildenafil were revealed in cocrystal structures, which provide structural templates for discovery of highly potent PDE5 inhibitors.