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1efy
From Proteopedia
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[[Image:1efy.jpg|left|200px]] | [[Image:1efy.jpg|left|200px]] | ||
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'''CRYSTAL STRUCTURE OF THE CATALYTIC FRAGMENT OF POLY (ADP-RIBOSE) POLYMERASE COMPLEXED WITH A BENZIMIDAZOLE INHIBITOR''' | '''CRYSTAL STRUCTURE OF THE CATALYTIC FRAGMENT OF POLY (ADP-RIBOSE) POLYMERASE COMPLEXED WITH A BENZIMIDAZOLE INHIBITOR''' | ||
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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:[http://www.ncbi.nlm.nih.gov/pubmed/11063605 11063605] | 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:[http://www.ncbi.nlm.nih.gov/pubmed/11063605 11063605] | ||
[[Category: Gallus gallus]] | [[Category: Gallus gallus]] | ||
| - | [[Category: NAD(+) ADP-ribosyltransferase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Almassy, R.]] | [[Category: Almassy, R.]] | ||
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[[Category: Srinivasan, S.]] | [[Category: Srinivasan, S.]] | ||
[[Category: White, A W.]] | [[Category: White, A W.]] | ||
| - | [[Category: | + | [[Category: Benzimidazole]] |
| - | [[Category: | + | [[Category: Catalytic fragment]] |
| - | [[Category: | + | [[Category: Crystal structure]] |
| - | [[Category: | + | [[Category: Inhibitor]] |
| - | [[Category: | + | [[Category: Polymerase]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 15:03:03 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 12:03, 2 May 2008
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. 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 Page seeded by OCA on Fri May 2 15:03:03 2008
