4MD6

Crystal structure of PDE5 in complex with inhibitor 5R


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.217 

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Ligand Structure Quality Assessment 


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Literature

Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure.

Shang, N.N.Shao, Y.X.Cai, Y.H.Guan, M.Huang, M.Cui, W.He, L.Yu, Y.J.Huang, L.Li, Z.Bu, X.Z.Ke, H.Luo, H.B.

(2014) Biochem Pharmacol 89: 86-98

  • DOI: https://doi.org/10.1016/j.bcp.2014.02.013
  • Primary Citation of Related Structures:  
    4MD6

  • PubMed Abstract: 

    Phosphodiesterase-5 (PDE5) inhibitors have been approved for the treatment of erectile dysfunction and pulmonary hypertension, but enthusiasm on discovery of PDE5 inhibitors continues for their potential new applications. Reported here is discovery of a series of new PDE5 inhibitors by structure-based design, molecular docking, chemical synthesis, and enzymatic characterization. The best compound, 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (57), has an IC₅₀ of 17 nM against the PDE5 catalytic domain and good selectivity over other PDE families. The crystal structure of the PDE5 catalytic domain in complex with 57 was determined at 2Å resolution and showed that 57 occupies the same pocket as other PDE5 inhibitors, but has a different binding pattern in detail. On the basis of the binding pattern of 57, a novel scaffold can be proposed as a candidate of PDE inhibitors.


  • Organizational Affiliation

    School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR 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
Binding Affinity Annotations 
IDSourceBinding Affinity
24E Binding MOAD:  4MD6 IC50: 17 (nM) from 1 assay(s)
BindingDB:  4MD6 IC50: 17 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.217 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.106α = 90
b = 74.106β = 90
c = 132.344γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
AMoREphasing
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-09
    Type: Initial release