6ACB

Crystal structure of PDE5 in complex with inhibitor LW1805


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.201 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

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.

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

(2018) J Med Chem 61: 8468-8473

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01209
  • Primary Citation of Related Structures:  
    5ZZ2, 6ACB

  • PubMed 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 IC 50 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.


  • Organizational Affiliation

    School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , P. R. China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cGMP-specific 3',5'-cyclic phosphodiesterase326Homo sapiensMutation(s): 0 
Gene Names: PDE5APDE5
EC: 3.1.4.35
UniProt & NIH Common Fund Data Resources
Find proteins for O76074 (Homo sapiens)
Explore O76074 
Go to UniProtKB:  O76074
PHAROS:  O76074
GTEx:  ENSG00000138735 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO76074
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9T9
Query on 9T9

Download Ideal Coordinates CCD File 
E [auth A]3-[(2H-1,3-benzodioxol-5-yl)methyl]-8-fluoro-6-{[2-(4-methylpiperazin-1-yl)ethyl]amino}-1-(1,3-thiazol-2-yl)[1]benzopyrano[2,3-c]pyrrol-9(2H)-one
C29 H28 F N5 O4 S
PRRCSWFEDVEDKN-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
D [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.201 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.577α = 90
b = 74.577β = 90
c = 132.092γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
CrysalisProdata reduction
CrysalisProdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Natural Science Foundation of ChinaChina81602955
National Natural Science Foundation of ChinaChina21702238

Revision History  (Full details and data files)

  • Version 1.0: 2018-09-19
    Type: Initial release
  • Version 1.1: 2018-10-10
    Changes: Data collection, Database references, Structure summary
  • Version 1.2: 2023-11-22
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary