1efy
From Proteopedia
(New page: 200px<br /><applet load="1efy" size="450" color="white" frame="true" align="right" spinBox="true" caption="1efy, resolution 2.2Å" /> '''CRYSTAL STRUCTURE OF ...) |
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| - | [[Image:1efy.jpg|left|200px]]<br /><applet load="1efy" size=" | + | [[Image:1efy.jpg|left|200px]]<br /><applet load="1efy" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1efy, resolution 2.2Å" /> | caption="1efy, resolution 2.2Å" /> | ||
'''CRYSTAL STRUCTURE OF THE CATALYTIC FRAGMENT OF POLY (ADP-RIBOSE) POLYMERASE COMPLEXED WITH A BENZIMIDAZOLE INHIBITOR'''<br /> | '''CRYSTAL STRUCTURE OF THE CATALYTIC FRAGMENT OF POLY (ADP-RIBOSE) POLYMERASE COMPLEXED WITH A BENZIMIDAZOLE INHIBITOR'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The nuclear enzyme poly(ADP-ribose) polymerase (PARP) facilitates the | + | 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== | ==About this Structure== | ||
| - | 1EFY is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus] with BZC as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/NAD(+)_ADP-ribosyltransferase NAD(+) ADP-ribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.30 2.4.2.30] Full crystallographic information is available from [http:// | + | 1EFY is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus] with <scene name='pdbligand=BZC:'>BZC</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/NAD(+)_ADP-ribosyltransferase NAD(+) ADP-ribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.30 2.4.2.30] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EFY OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Almassy, R.]] | [[Category: Almassy, R.]] | ||
| - | [[Category: Calvert, A | + | [[Category: Calvert, A H.]] |
| - | [[Category: Curtin, N | + | [[Category: Curtin, N J.]] |
| - | [[Category: Golding, B | + | [[Category: Golding, B T.]] |
| - | [[Category: Griffin, R | + | [[Category: Griffin, R J.]] |
[[Category: Hostomsky, Z.]] | [[Category: Hostomsky, Z.]] | ||
[[Category: Maegley, K.]] | [[Category: Maegley, K.]] | ||
| - | [[Category: Newell, D | + | [[Category: Newell, D R.]] |
[[Category: Srinivasan, S.]] | [[Category: Srinivasan, S.]] | ||
| - | [[Category: White, A | + | [[Category: White, A W.]] |
[[Category: BZC]] | [[Category: BZC]] | ||
[[Category: benzimidazole]] | [[Category: benzimidazole]] | ||
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[[Category: polymerase]] | [[Category: polymerase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:27:21 2008'' |
Revision as of 10:27, 21 February 2008
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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 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
Page seeded by OCA on Thu Feb 21 12:27:21 2008
Categories: Gallus gallus | NAD(+) ADP-ribosyltransferase | Single protein | Almassy, R. | Calvert, A H. | Curtin, N J. | Golding, B T. | Griffin, R J. | Hostomsky, Z. | Maegley, K. | Newell, D R. | Srinivasan, S. | White, A W. | BZC | Benzimidazole | Catalytic fragment | Crystal structure | Inhibitor | Polymerase
