Journal of APPLIED BIOMEDICINE
ISSN 1214-0287 (on-line)
ISSN 1214-021X (printed)

Volume 3 (2005), No 3, p 139-145




Prediction of a new broad-spectrum reactivator capable to of reactivatinge acetylcholinesterase inhibited by nerve agents

Vlastimil Dohnal, Kamil Kuca, Daniel Jun

Address: Kamil Kuca, Department of Toxicology, School of Military Health Sciences, Trebesska 1575, University of Defence, 500 01 Hradec Kralove, Czech Republic
kucakam@pmfhk.cz

Received 23rd May 2005.
Published online 10th September 2005.

Full text article (pdf)

SUMMARY
A methodology combining molecular structure represented by fragments, and artificial neural network (ANN) was applied for the prediction of a new acetylcholinesterase (AChE; EC 3.1.1.7) reactivator. We searched for a new structure of the AChE reactivator with the capability of reactivating AChE inhibited by almost all actual nerve agents. For this purpose, we have tested in vitro seventeen potential AChE reactivators for reactivation of AChE inhibited by sarin, cyclosarin, agent VX and tabun. The results obtained were used as input data for prediction by ANN. Using ANN we have predicted new AChE reactivators.

KEY WORDS
oxime; acetylcholinesterase; reactivation; artificial neural networks; organophosphates; QSAR


REFERENCES
Bajgar J: Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. Adv Clin Chem 38:151-216, 2004.

Basheer IA, Hajmeer M: Artificial neural networks: fundamentals, computing, design, and application. J Microbiol Methods 43:3-31, 2000.

Brodnjak-Voncina D, Dobcnik D, Novic M, Zupan J: Determination of concentrations at hydrolytic potentiometric titrations with models made by artificial neural networks. Chemom Intell Lab Syst 47:79-88, 1999.

Dohnal V, Zhang F, Li H, Havel J: Quantitative chiral analysis in capillary electrophoresis from unresolved peaks using derivative electropherograms, experimental design, and artificial neural networks. Electrophoresis 24:2462-2468, 2003.

Farkova M, Pena EM, Havel J: Use of artificial neural networks in capillary zone electrophoresis. J Chromatogr A 848:365-374, 1999.

Hameda AB, Elosta S, Havel J: Optimization of the capillary zone electrophoresis method for Huperzine A determination using experimental design and artificial neural networks. J Chromatogr A - in press.

Hemmateenejad B: Correlation ranking procedure for factor selection in PC-ANN modeling and application to ADMETox evaluation. Chemom Intell Lab Syst 75:231-245, 2005.

Hemmateenejad B, Miri R, Akhond M, Shamsipur M: QSAR study of the calcium channel antagonist activity of some recently synthesized dihydropyridine derivatives. An application of genetic algorithm for variable selection in MLR and PLS methods. Chemom Intell Lab Syst 64:91-99, 2002.

Kassa J: Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents. J Toxicol Clin Toxicol 40:803-816, 2002.

Kuca K, Kassa J: A comparison of the ability of a new bispyridinium oxime-1-(4- hydroxyiminomethylpyridinium)-4-(4- carbamoylpyridinium) butane dibromide and currently used oximes to reactivate nerve agent-inhibited rat brain acetylcholinesterase by in vitro methods. J Enz Inh Med Chem 18:529-535, 2003.

Kuca K, Bielavsky J, Cabal J, Kassa J: Synthesis of a new reactivator of tabun inhibited acetylcholinesterase. Bioorg Med Chem Lett 13:3545-3547, 2003.

Kuca K, Cabal J, Bajgar J, Jun D: In vitro searching for a new potent reactivator of acetylcholinesterase inhibited by nerve agent VX. Lett Drug Design Discovery 2:23-25, 2005.

Lek S, Guegan JF: Artificial neural networks as a tool in ecological modelling, an introduction. Ecol Modell 120:65-73, 1999.

Luongo G, Marandola C, Mazzarella A: Neural forecasting of seismicity and ground displacements in different volcanic areas. J Volcan Geotherm Res 130:133-146, 2004.

Marrs TC: Organophosphate poisoning. Pharmacol Ther 58:51-66, 1993.

McClelland JL, Rumelhart DE: Explorations in Parallel Distributed Processing., MIT Press, Cambridge, 1988.

McCulloch W, Pitts W: A logical calculus of the ideas immanent in nervous activity. Bull Math Biophys 5:115-133, 1943.

Patocka J, Kuca K, Jun D: Acetylcholinesterase: crucial enzyme of human body. Acta Medica (Hradec Kralove) 47:215-230, 2004.

Ramirez MCV, Velho HFC, Ferreira NJ: Artificial neural network technique for rainfall forecasting applied to the Sao Paulo region. J Hydrology 301:146-162, 2005.

Turner JV, Maddalena DJ, Cutler DJ: Pharmacokinetic parameter prediction from drug structure using artificial neural networks. Int J Pharm 270:209-219, 2004.

Wold S, Sjostrom M, Eriksson L: PLS-regression: a basic tool of chemometrics. Chemom Intell Lab Syst 58:109-130, 2001.
CITED

Cetina M, Nagl A, Gaso-Sokac D, Kovac S, Busic V, Saftic D. Extensive Intramolecular and Intermolecular Interactions in Two Quaternary Salts of the Pyridoxal Oxime. J Chem Crystallogr. 42: 752-758, 2012.

Kassa J, Musilek K, Karasova JZ, Kuca K, Bajgar J. Two possibilities how to increase the efficacy of antidotal treatment of nerve agent poisonings. Mini-Rev Med Chem. 12: 24-34, 2012.

Kuca K, Cabal J, Jung YS, Musilek K, Soukup O, Jun D, Pohanka M, Musilova L, Karasova J, Novotny L, Hrabinova M. Reactivation of Human Brain Homogenate Cholinesterases Inhibited by Tabun using Newly Developed Oximes K117 and K127. Basic Clin Pharmacol Toxicol. 105: 207-210, 2009.

Kassa J, Karasova JZ, Musilek K, Kuca K, Jung YS. A comparison of the neuroprotective efficacy of newly developed oximes (K117, K127) and currently available oxime (obidoxime) in tabun-poisoned rats. Toxicol Mechanisms Methods. 19: 232-238, 2009.

Kassa J, Karasova J, Vasina L, Bajgar J, Kuca K, Musilek K. A Comparison of neuroprotective efficacy of newly developed oximes (K203, K206) and commonly used oximes (obidoxime, HI-6) in tabun-poisoned rats. Drug Chem Toxicol. 32: 128-138, 2009.

Kuca K, Jun D, Bajgar J. Structural factors influencing potency of currently used acetylc holineste rase reactivators for treatment of cyclosarin intoxications. Curr Pharm Design. 13: 3445-3452, 2007.

Kassa J, Karasova J. The evaluation of the neuroprotective effects of bispyridinium oximes in Tabun-poisoned rats. J Toxicol Environ Health Part A. 70: 1556-1567, 2007.

Hoskovcova M, Halamek E, Kobliha Z, Tusarova I. Reactivation of immobilized acetylcholinesterase-tabun complex by methoxime and its homologues. Drug Chem Toxicol. 30: 97-103, 2007.

Kassa J, Kuca K, Bartosova L, Kunesova G. The development of new structural analogues of oximes for the antidotal treatment of poisoning by nerve agents and the comparison of their reactivating and therapeutic efficacy with currently available oximes. Curr Org Chem. 11: 267-283, 2007.

Kassa J, Kunesova G. Comparison of the neuroprotective effects of the newly developed oximes (K027, K048) with trimedoxime in tabun-poisoned rats. J Appl Biomed. 4: 123-134, 2006.

Kuca K, Cabal J, Jun D, Hrabinova M. In vitro evaluation of acetylcholinesterase reactivators as potential antidotes against tabun nerve agent poisonings. Drug Chem Toxicol. 29: 443-449, 2006.

Kuca K, Jun D, Kim TH, Cabal J, Jung Y-S. In vitro evaluation of new acetylcholinesterase reactivators as casual antidotes against tabun and cyclosarin. Bull Korean Chem Soc. 27: 395-398, 2006.

Kim T-H, Oh K-A, Park N-J, Park N-S, Kim YJ, Yum EK, Jung Y-S. Reactivation study of pyridinium oximes for acetylcholinesterases inhibited by paraoxon or DFP. J Appl Biomed. 4: 67-72, 2006.

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