4OQA: Structure of Human PARP-1 bound to a DNA double strand break in complex with (2Z)-2-(2,4-dihydroxybenzylidene)-3-oxo-2,3-dihydro-1-benzofuran-7-carboxamide

Citation:
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 muM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 muM). 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 muM) 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 muM). 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.
PDB ID: 4OQADownload
MMDB ID: 121174
PDB Deposition Date: 2014/2/7
Updated in MMDB: 2017/07
Experimental Method:
x-ray diffraction
Resolution: 3.65  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 4OQA: tetrameric; determined by author
Molecular Components in 4OQA
Label Count Molecule
Proteins (2 molecules)
1
Poly [adp-ribose] Polymerase 1(Gene symbol: PARP1)
Molecule annotation
1
Poly [adp-ribose] Polymerase 1(Gene symbol: PARP1)
Molecule annotation
Nucleotide(1 molecule)
2
DNA (26-mer)
Molecule annotation
Chemicals (3 molecules)
1
2
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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