期刊
JOURNAL OF INORGANIC BIOCHEMISTRY
卷 134, 期 -, 页码 12-19出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2013.12.011
关键词
Acetylcholinesterase reactivators; Docking simulations; Zinc complexes; Organophosphorus compounds; Crystal structures; Pyridyl oximes
资金
- Research Committee of the University of Patras [C584]
- Alexander von Humboldt Foundation for a postdoctoral research fellowship
In order to investigate the ability of metal complexes to act as reactivators of organophosphorus compounds (OP)-inhibited acetylcholinesterase (AChE), we have synthesized and crystallographically characterized three novel mononuclear Zn-II complexes formulated as [ZnCl2{(4-py)CHNOH}(2)] (1), [ZnBr2{(4-py)CHNOH)(2)] (2) and [Zn(O2CMe)(2)((4-py)CHNOH}(2)]center dot 2MeCN (3 center dot 2MeCN), where (4-py)CHNOH is 4-pyridinealdoxime. Their reactivation potency was tested in vitro with a slight modification of the Ellman's method using Electric eel acetylcholinesterase and the insecticide paraoxon (diethyl 4-nitrophenyl phosphate) as inhibitor. The activity of the already reported complex [Zn-2(O2CPh)(2){(4-Py)CHNOH}(2)]center dot 2MeCN (4 center dot 2MeCN) and of the clinically used drug obidoxime 1,1'-[oxybis(methylene)]bis(4-[(E)-(hydroxyimino)methyllpyridinium) was also examined. The results of the in vitro experiments demonstrate moderate reactivation of the metal complexes compared to the drug obidoxime. On the other hand, it is clearly shown that the metal complex is the responsible molecular entity for the observed activity, as the reactivation efficacy of the organic ligand (4-pyridinealdoxime) is found to be inconsequential. Docking simulation studies were performed in the light of predicted complex-enzyme interactions using the paraoxon-inhibited enzyme along with the four Zn-II complexes and obidoxime as a reference reactivator. The results showed that the three mononuclear metal complexes possess the required characteristics to be accommodated into the active site of AChE, while the entrance of the dinuclear Zn-II compound is unsuccessful. An interesting outcome of docking simulations is the fact that the mononuclear compounds accommodate into the active site of AChE in a similar mode as obidoxime. (c) 2014 Elsevier Inc. All rights reserved.
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