1efy

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spinqualitylabelsall models 1efy, resolution 2.2Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF THE CATALYTIC FRAGMENT OF POLY (ADP-RIBOSE) POLYMERASE COMPLEXED WITH A BENZIMIDAZOLE INHIBITOR

Overview

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) facilitates the, repair of DNA strand breaks and is implicated in the resistance of cancer, cells to certain DNA-damaging agents. Inhibitors of PARP have clinical, potential as resistance-modifying agents capable of potentiating, radiotherapy and the cytotoxicity of some forms of cancer chemotherapy., The preclinical development of 2-aryl-1H-benzimidazole-4-carboxamides as, resistance-modifying agents in cancer chemotherapy is described., 1H-Benzimidazole-4-carboxamides, particularly 2-aryl derivatives, are, identified as a class of potent PARP inhibitors. Derivatives of, 2-phenyl-1H-benzimidazole-4-carboxamide (23, K(i) = 15 nM), in which the, phenyl ring contains substituents, have been synthesized. Many of these, derivatives exhibit K(i) values for PARP inhibition < 10 nM, with, 2-(4-hydroxymethylphenyl)-1H-benzimidazole-4-carboxamide (78, K(i) = 1.6, nM) being one of the most potent. Insight into structure-activity, relationships (SAR) for 2-aryl-1H-benzimidazole-4-carboxamides has been, enhanced by studying the complex formed between, 2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide (44, K(i) = 6 nM) and, the catalytic domain of chicken PARP. Important hydrogen-bonding and, hydrophobic interactions with the protein have been identified for this, inhibitor. 2-(4-Hydroxyphenyl)-1H-benzimidazole-4-carboxamide (45, K(i) =, 6 nM) potentiates the cytotoxicity of both temozolomide and topotecan, against A2780 cells in vitro (by 2.8- and 2.9-fold, respectively).

About this Structure

1EFY is a Single protein structure of sequence from Gallus gallus with BZC as ligand. Active as NAD(+) ADP-ribosyltransferase, with EC number 2.4.2.30 Full crystallographic information is available from OCA.

Reference

Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase., White AW, Almassy R, Calvert AH, Curtin NJ, Griffin RJ, Hostomsky Z, Maegley K, Newell DR, Srinivasan S, Golding BT, J Med Chem. 2000 Nov 2;43(22):4084-97. PMID:11063605

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