A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition
Authorized Users Only
2020
Authors
Bondžić, Aleksandra M.
Lazarević-Pašti, Tamara D.

Leskovac, Andreja R.

Petrović, Sandra

Čolović, Mirjana B.

Parac-Vogt Tatjana

Janjić, Goran

Article (Published version)

Elsevier
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Show full item recordAbstract
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 β-allosteric site (β-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 WS...iA 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.
Keywords:
AChE / New β-allosteric site / Genotoxicity / Docking study / PolyoxometalatesSource:
European Journal of Pharmaceutical Sciences, 2020, 151, 105376-Publisher:
- Elsevier
Funding / projects:
- Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200026 (University of Belgrade, Institute of Chemistry, Technology and Metallurgy - IChTM) (RS-200026)
- Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200017 (University of Belgrade, Institute of Nuclear Sciences 'Vinča', Belgrade-Vinča) (RS-200017)
- COST action CM1203 Polyoxometalate Chemistry for Molecular Nanoscience (PoCheMoN), ECOST-STSM-CM1203-041015-063147-63147
- COST action CM1203 Polyoxometalate Chemistry for Molecular Nanoscience (PoCheMoN), COST-STSM-ECOST-STSM-CM1203-030416-072554
DOI: 10.1016/j.ejps.2020.105376
ISSN: 0928-0987
PubMed: 32492460
WoS: 000545890200005
Scopus: 2-s2.0-85085760261
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Institution/Community
IHTMTY - JOUR AU - Bondžić, Aleksandra M. AU - Lazarević-Pašti, Tamara D. AU - Leskovac, Andreja R. AU - Petrović, Sandra AU - Čolović, Mirjana B. AU - Parac-Vogt Tatjana AU - Janjić, Goran PY - 2020 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/3582 AB - 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 β-allosteric site (β-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. PB - Elsevier T2 - European Journal of Pharmaceutical Sciences T1 - A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition VL - 151 SP - 105376 DO - 10.1016/j.ejps.2020.105376 ER -
@article{ author = "Bondžić, Aleksandra M. and Lazarević-Pašti, Tamara D. and Leskovac, Andreja R. and Petrović, Sandra and Čolović, Mirjana B. and Parac-Vogt Tatjana and Janjić, Goran", year = "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 β-allosteric site (β-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.", publisher = "Elsevier", journal = "European Journal of Pharmaceutical Sciences", title = "A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition", volume = "151", pages = "105376", doi = "10.1016/j.ejps.2020.105376" }
Bondžić, A. M., Lazarević-Pašti, T. D., Leskovac, A. R., Petrović, S., Čolović, M. B., Parac-Vogt Tatjana,& Janjić, G.. (2020). A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition. in European Journal of Pharmaceutical Sciences Elsevier., 151, 105376. https://doi.org/10.1016/j.ejps.2020.105376
Bondžić AM, Lazarević-Pašti TD, Leskovac AR, Petrović S, Čolović MB, Parac-Vogt Tatjana, Janjić G. A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition. in European Journal of Pharmaceutical Sciences. 2020;151:105376. doi:10.1016/j.ejps.2020.105376 .
Bondžić, Aleksandra M., Lazarević-Pašti, Tamara D., Leskovac, Andreja R., Petrović, Sandra, Čolović, Mirjana B., Parac-Vogt Tatjana, Janjić, Goran, "A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition" in European Journal of Pharmaceutical Sciences, 151 (2020):105376, https://doi.org/10.1016/j.ejps.2020.105376 . .