A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules – the role in the mechanism of AChE inhibition
Само за регистроване кориснике
2020
Аутори
Bondžić, Aleksandra M.Lazarević-Pašti, Tamara
Leskovac, Andreja
Petrović, Sandra
Čolović, Mirjana B.
Parac-Vogt, Tatjana N.
Janjić, Goran V.
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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 andtryptophan fluorescence spectroscopy demonstrated that the AChE inhibition was not accompanied by significantchanges in the secondary structure of the enzyme. The molecular docking approach has revealed a newallosteric binding site, termed β-allosteric site (β-AS), which is considered responsible for the inhibition of AChEby POMs. To the best of our knowledge, this is the first study reporting a new allosteric site that is consideredresponsible for AChE inhibition by voluminous and negatively charged molecules such as POMs. The selectedPOMs were further subjected to genotoxicity testing using human peripheral blood cells as a model system. Itwas shown that WSiA and WPA induced... a mild cytostatic but not genotoxic effects in human lymphocytes, whichindicates their potential to be used as medicinal drugs. The identification of non-toxic compounds capable ofbinding to an allosteric site that so far has not been considered responsible for enzyme inhibition could befundamental for the development of new drug design strategies and the discovery of more efficient AChEmodulators.
Кључне речи:
AChE / New β-allosteric site / Genotoxicity / Docking study / PolyoxometalatesИзвор:
European Journal of Pharmaceutical Sciences, 2020, 151, 105376-Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200026 (Универзитет у Београду, Институт за хемију, технологију и металургију - ИХТМ) (RS-200026)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200017 (Универзитет у Београду, Институт за нуклеарне науке Винча, Београд-Винча) (RS-200017)
- CMST COST Action [CM1203 (PoCheMoN)]
- 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-s2.0-8508576026
Институција/група
VinčaTY - JOUR AU - Bondžić, Aleksandra M. AU - Lazarević-Pašti, Tamara AU - Leskovac, Andreja AU - Petrović, Sandra AU - Čolović, Mirjana B. AU - Parac-Vogt, Tatjana N. AU - Janjić, Goran V. PY - 2020 UR - https://vinar.vin.bg.ac.rs/handle/123456789/9028 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 andtryptophan fluorescence spectroscopy demonstrated that the AChE inhibition was not accompanied by significantchanges in the secondary structure of the enzyme. The molecular docking approach has revealed a newallosteric binding site, termed β-allosteric site (β-AS), which is considered responsible for the inhibition of AChEby POMs. To the best of our knowledge, this is the first study reporting a new allosteric site that is consideredresponsible for AChE inhibition by voluminous and negatively charged molecules such as POMs. The selectedPOMs were further subjected to genotoxicity testing using human peripheral blood cells as a model system. Itwas shown that WSiA and WPA induced a mild cytostatic but not genotoxic effects in human lymphocytes, whichindicates their potential to be used as medicinal drugs. The identification of non-toxic compounds capable ofbinding to an allosteric site that so far has not been considered responsible for enzyme inhibition could befundamental for the development of new drug design strategies and the discovery of more efficient AChEmodulators. 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 and Leskovac, Andreja and Petrović, Sandra and Čolović, Mirjana B. and Parac-Vogt, Tatjana N. and Janjić, Goran V.", 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 andtryptophan fluorescence spectroscopy demonstrated that the AChE inhibition was not accompanied by significantchanges in the secondary structure of the enzyme. The molecular docking approach has revealed a newallosteric binding site, termed β-allosteric site (β-AS), which is considered responsible for the inhibition of AChEby POMs. To the best of our knowledge, this is the first study reporting a new allosteric site that is consideredresponsible for AChE inhibition by voluminous and negatively charged molecules such as POMs. The selectedPOMs were further subjected to genotoxicity testing using human peripheral blood cells as a model system. Itwas shown that WSiA and WPA induced a mild cytostatic but not genotoxic effects in human lymphocytes, whichindicates their potential to be used as medicinal drugs. The identification of non-toxic compounds capable ofbinding to an allosteric site that so far has not been considered responsible for enzyme inhibition could befundamental for the development of new drug design strategies and the discovery of more efficient AChEmodulators.", 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., Leskovac, A., Petrović, S., Čolović, M. B., Parac-Vogt, T. N.,& Janjić, G. V.. (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, 151, 105376. https://doi.org/10.1016/j.ejps.2020.105376
Bondžić AM, Lazarević-Pašti T, Leskovac A, Petrović S, Čolović MB, Parac-Vogt TN, Janjić GV. 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, Leskovac, Andreja, Petrović, Sandra, Čolović, Mirjana B., Parac-Vogt, Tatjana N., Janjić, Goran V., "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 . .