Lazarevic-Pasti TD

References (3)

Title : A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules - the role in the mechanism of AChE inhibition - Bondzic_2020_Eur.J.Pharm.Sci_151_105376
Author(s) : Bondzic AM , Lazarevic-Pasti TD , Leskovac AR , Petrovic SZ , Colovic MB , Parac-Vogt TN , Janjic GV
Ref : Eur J Pharm Sci , 151 :105376 , 2020
Abstract : Acetylcholinesterase (AChE) inhibitors are important in the treatment of neurodegenerative diseases. Two inhibitors, 12-tungstosilicic acid (WSiA) and 12-tungstophosphoric acid (WPA), which have polyoxometalate (POM) type structure, have been shown to inhibit AChE activity in nM concentration. Circular dichroism and tryptophan fluorescence spectroscopy demonstrated that the AChE inhibition was not accompanied by significant changes in the secondary structure of the enzyme. The molecular docking approach has revealed a new allosteric binding site, termed beta-allosteric site (beta-AS), which is considered responsible for the inhibition of AChE by POMs. To the best of our knowledge, this is the first study reporting a new allosteric site that is considered responsible for AChE inhibition by voluminous and negatively charged molecules such as POMs. The selected POMs were further subjected to genotoxicity testing using human peripheral blood cells as a model system. It was shown that WSiA and WPA induced a mild cytostatic but not genotoxic effects in human lymphocytes, which indicates their potential to be used as medicinal drugs. The identification of non-toxic compounds capable of binding to an allosteric site that so far has not been considered responsible for enzyme inhibition could be fundamental for the development of new drug design strategies and the discovery of more efficient AChE modulators.
ESTHER : Bondzic_2020_Eur.J.Pharm.Sci_151_105376
PubMedSearch : Bondzic_2020_Eur.J.Pharm.Sci_151_105376
PubMedID: 32492460

Title : Acetylcholinesterase inhibitors: pharmacology and toxicology - Colovic_2013_Curr.Neuropharmacol_11_315
Author(s) : Colovic MB , Krstic DZ , Lazarevic-Pasti TD , Bondzic AM , Vasic VM
Ref : Curr Neuropharmacol , 11 :315 , 2013
Abstract : Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer's disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases.
ESTHER : Colovic_2013_Curr.Neuropharmacol_11_315
PubMedSearch : Colovic_2013_Curr.Neuropharmacol_11_315
PubMedID: 24179466

Title : Indirect electrochemical oxidation of organophosphorous pesticides for efficient detection via acetylcholinesterase test - Lazarevic-Pasti_2012_Pestic.Biochem.Physiol_104_236
Author(s) : Lazarevic-Pasti TD , Bondzic AM , Pasti IA , Vasic VM
Ref : Pesticide Biochemistry and Physiology , 104 :236 , 2012
Abstract : Organothiophosphorous pesticides diazinon, malathion, chlorpyrifos, azinphos-methyl and phorate, have been indirectly electrochemically oxidized in aqueous media using anodically evolved Cl2, Br2 or I2 as a pre-step for their detection via acetylcholinesterase-based test. The presence of single oxidation product, corresponding oxo-form, was confirmed by UPLC analysis, as well as its stability with respect to hydrolysis. Comparing different halogens, the best results were obtained using Br2 as the oxidant due to high reactivity of HOBr, which is formed upon chemical reaction of anodically formed Br2 with water. Limits of detection of five analyzed pesticides were lowered upon indirect electrochemical oxidation with Br2 for two orders of magnitude or more, comparing to unoxidized parental thio-forms. In fact, the lowest possible detection limits for all five pesticides using proposed analytical procedure were achieved, as being determined by detection limits of corresponding oxo forms. Comparison of here proposed electrochemical oxidation pre-step with earlier reported ones is provided and discussed.
ESTHER : Lazarevic-Pasti_2012_Pestic.Biochem.Physiol_104_236
PubMedSearch : Lazarevic-Pasti_2012_Pestic.Biochem.Physiol_104_236