title: Zn(II)/pyridyloxime complexes as potential reactivators of OP-inhibited acetylcholinesterase: in vitro and docking simulation studies.
abstract: 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]∙2MeCN (3∙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 [Zn2(O2CPh)2{(4-py)CHNOH}2]·2MeCN (4·2MeCN) and of the clinically used drug obidoxime 1,1'-[oxybis(methylene)]bis{4-[(E)- (hydroxyimino)methyl]pyridinium} 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.
authors: Department of Chemistry, University of Patras, 265 04 Patras, Greece; Institute of Nanotechnology, Karlsruhe Institute of Technology, Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen, Germany. Electronic address: konstantis.konidaris@partner.kit.edu.
authors: Konstantis F
authors: KF
authors: Konidaris
authors: Department of Pharmacy, University of Patras, 26504 Patras, Greece.
authors: Georgios A
authors: GA
authors: Dalkas
authors: Department of Chemistry, University of Patras, 265 04 Patras, Greece.
authors: Eugenia
authors: E
authors: Katsoulakou
authors: Department of Pharmacy, University of Patras, 26504 Patras, Greece.
authors: George
authors: G
authors: Pairas
authors: Institute of Materials Science, NCSR "Demokritos", 153 10 Aghia Paraskevi Attikis, Greece.
authors: Catherine P
authors: CP
authors: Raptopoulou
authors: Department of Pharmacy, University of Patras, 26504 Patras, Greece.
authors: Fotini N
authors: FN
authors: Lamari
authors: Department of Pharmacy, University of Patras, 26504 Patras, Greece.
authors: Georgios A
authors: GA
authors: Spyroulias
authors: Department of Chemistry, University of Patras, 265 04 Patras, Greece. Electronic address: emane@upatras.gr.
authors: Evy
authors: E
authors: Manessi-Zoupa
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000818:Animals; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry; D002801:Cholinesterase Reactivators / Q000138:chemical synthesis / Q000737:chemistry*; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004524:Eels; D029941:Fish Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D007306:Insecticides / Q000737:chemistry; D008024:Ligands; D062105:Molecular Docking Simulation; D009768:Obidoxime Chloride / Q000737:chemistry; D010091:Oximes / Q000737:chemistry*; D010261:Paraoxon / Q000737:chemistry; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D056831:Coordination Complexes; D029941:Fish Proteins; D007306:Insecticides; D008024:Ligands; D010091:Oximes; D009768:Obidoxime Chloride; C050580:pyridine-4-aldoxime; D000110:Acetylcholinesterase; D015032:Zinc; D010261:Paraoxon
keywords: Acetylcholinesterase reactivators; Crystal structures; Docking simulations; Organophosphorus compounds; Pyridyl oximes; Zinc complexes