4OPX

Structure of Human PARP-1 bound to a DNA double strand break in complex with (2R)-5-fluoro-2-methyl-2,3-dihydro-1-benzofuran-7-carboxamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.31 Å
  • R-Value Free: 0.325 
  • R-Value Work: 0.303 
  • R-Value Observed: 0.304 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery and Structure-Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors.

Patel, M.R.Bhatt, A.Steffen, J.D.Chergui, A.Murai, J.Pommier, Y.Pascal, J.M.Trombetta, L.D.Fronczek, F.R.Talele, T.T.

(2014) J Med Chem 57: 5579-5601

  • DOI: https://doi.org/10.1021/jm5002502
  • Primary Citation of Related Structures:  
    4OPX, 4OQA, 4OQB

  • PubMed Abstract: 

    Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3',4'-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4'-hydroxyl/4'-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66-68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (-)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.


  • Organizational Affiliation

    Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University , Queens, New York 11439, United States.


Macromolecules

Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Poly [ADP-ribose] polymerase 1A,
C [auth D]
267Homo sapiensMutation(s): 0 
Gene Names: PARP1ADPRTPPOL
UniProt & NIH Common Fund Data Resources
Find proteins for P09874 (Homo sapiens)
Explore P09874 
Go to UniProtKB:  P09874
PHAROS:  P09874
GTEx:  ENSG00000143799 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP09874
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Poly [ADP-ribose] polymerase 1B [auth C],
D [auth F]
505Homo sapiensMutation(s): 0 
Gene Names: PARP1ADPRTPPOL
EC: 2.4.2.30
UniProt & NIH Common Fund Data Resources
Find proteins for P09874 (Homo sapiens)
Explore P09874 
Go to UniProtKB:  P09874
PHAROS:  P09874
GTEx:  ENSG00000143799 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP09874
Sequence Annotations
Expand
  • Reference Sequence
Find similar nucleic acids by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains LengthOrganismImage
DNA (26-MER)E [auth M],
F [auth N]
26N/A
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.31 Å
  • R-Value Free: 0.325 
  • R-Value Work: 0.303 
  • R-Value Observed: 0.304 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65.15α = 90
b = 112.91β = 90
c = 295.29γ = 90
Software Package:
Software NamePurpose
CBASSdata collection
REFMACrefinement
xia2data reduction
xia2data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-02
    Type: Initial release
  • Version 1.1: 2014-07-09
    Changes: Database references
  • Version 1.2: 2014-07-23
    Changes: Database references
  • Version 1.3: 2017-07-26
    Changes: Source and taxonomy
  • Version 1.4: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description