TY  - JOUR
AU  - Bondžić, Aleksandra
AU  - Senćanski, Milan
AU  - Vujačić Nikezić, Ana V.
AU  - Kirillova, Marina V.
AU  - André, Vânia
AU  - Kirillov, Alexander M.
AU  - Bondžić, Bojan
PY  - 2020
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/3958
AB  - Three coordination compounds featuring different types of tetracopper(II) cores, namely
[O⊂Cu4{N(CH2CH2O)3}4(BOH)4][BF4]2 (1), [Cu4(μ4-H2edte)(μ5-H2edte)(sal)2]n·7nH2O, (H4edte=N,N,N′,
N′-tetrakis(2-hydroxyethyl)ethylenediamine, H2sal=salicylic acid) (2), and [{Cu4(μ3-Hbes)4(μ-hba)}K
(H2O)3]n, H3bes=N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (3), were assayed for their potency to
inhibit the acetyl (AChE) and butyrylcholinesterase (BuChE) enzymes aiming to test these compounds as potential
dual inhibitors in the treatment of Alzheimer's disease. All the investigated compounds showed a strong
inhibitory potency toward both enzymes with IC50 values in micromolar range of concentration; compound 1
displayed the most potent inhibitory behaviour toward both enzymes. The mechanism of the AChE and BuChE
inhibition was examined by enzyme kinetic measurements. The obtained kinetic parameters, Vmax and Km indicated
an uncompetitive type of inhibition of both enzymes by compound 1. For the other two compounds a
non-competitive inhibition mode was observed. To get further insight into the mechanism of action and to
elucidate binding modes in details we examined the interactions of 1–3 with acetylcholinesterase, using molecular
docking approach. Grid based docking studies indicated that these compounds can bind to peripheral
anionic site (PAS) of the AChE with Ki values in micromolar range. Moreover, blind docking revealed the
capability of investigated compounds to bind to new allosteric site (i.e. binding site II) distinct from PAS.
Showing that these Cu-based compounds can act as new allosteric inhibitors of AChE and identifying novel
allosteric binding site on AChE represents a significant contribution toward the design of novel and more
effective inhibitors of AChE.
PB  - Elsevier
T2  - Journal of Inorganic Biochemistry
T1  - Aminoalcoholate-driven tetracopper(II) cores as dual acetyl and butyrylcholinesterase inhibitors: Experimental and theoretical elucidation of mechanism of action
VL  - 205
SP  - 110990
DO  - 10.1016/j.jinorgbio.2019.110990
ER  - 

@article{
author = "Bondžić, Aleksandra and Senćanski, Milan and Vujačić Nikezić, Ana V. and Kirillova, Marina V. and André, Vânia and Kirillov, Alexander M. and Bondžić, Bojan",
year = "2020",
abstract = "Three coordination compounds featuring different types of tetracopper(II) cores, namely
[O⊂Cu4{N(CH2CH2O)3}4(BOH)4][BF4]2 (1), [Cu4(μ4-H2edte)(μ5-H2edte)(sal)2]n·7nH2O, (H4edte=N,N,N′,
N′-tetrakis(2-hydroxyethyl)ethylenediamine, H2sal=salicylic acid) (2), and [{Cu4(μ3-Hbes)4(μ-hba)}K
(H2O)3]n, H3bes=N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (3), were assayed for their potency to
inhibit the acetyl (AChE) and butyrylcholinesterase (BuChE) enzymes aiming to test these compounds as potential
dual inhibitors in the treatment of Alzheimer's disease. All the investigated compounds showed a strong
inhibitory potency toward both enzymes with IC50 values in micromolar range of concentration; compound 1
displayed the most potent inhibitory behaviour toward both enzymes. The mechanism of the AChE and BuChE
inhibition was examined by enzyme kinetic measurements. The obtained kinetic parameters, Vmax and Km indicated
an uncompetitive type of inhibition of both enzymes by compound 1. For the other two compounds a
non-competitive inhibition mode was observed. To get further insight into the mechanism of action and to
elucidate binding modes in details we examined the interactions of 1–3 with acetylcholinesterase, using molecular
docking approach. Grid based docking studies indicated that these compounds can bind to peripheral
anionic site (PAS) of the AChE with Ki values in micromolar range. Moreover, blind docking revealed the
capability of investigated compounds to bind to new allosteric site (i.e. binding site II) distinct from PAS.
Showing that these Cu-based compounds can act as new allosteric inhibitors of AChE and identifying novel
allosteric binding site on AChE represents a significant contribution toward the design of novel and more
effective inhibitors of AChE.",
publisher = "Elsevier",
journal = "Journal of Inorganic Biochemistry",
title = "Aminoalcoholate-driven tetracopper(II) cores as dual acetyl and butyrylcholinesterase inhibitors: Experimental and theoretical elucidation of mechanism of action",
volume = "205",
pages = "110990",
doi = "10.1016/j.jinorgbio.2019.110990"
}

Bondžić, A., Senćanski, M., Vujačić Nikezić, A. V., Kirillova, M. V., André, V., Kirillov, A. M.,& Bondžić, B.. (2020). Aminoalcoholate-driven tetracopper(II) cores as dual acetyl and butyrylcholinesterase inhibitors: Experimental and theoretical elucidation of mechanism of action. in Journal of Inorganic Biochemistry
Elsevier., 205, 110990.
https://doi.org/10.1016/j.jinorgbio.2019.110990

Bondžić A, Senćanski M, Vujačić Nikezić AV, Kirillova MV, André V, Kirillov AM, Bondžić B. Aminoalcoholate-driven tetracopper(II) cores as dual acetyl and butyrylcholinesterase inhibitors: Experimental and theoretical elucidation of mechanism of action. in Journal of Inorganic Biochemistry. 2020;205:110990.
doi:10.1016/j.jinorgbio.2019.110990 .

Bondžić, Aleksandra, Senćanski, Milan, Vujačić Nikezić, Ana V., Kirillova, Marina V., André, Vânia, Kirillov, Alexander M., Bondžić, Bojan, "Aminoalcoholate-driven tetracopper(II) cores as dual acetyl and butyrylcholinesterase inhibitors: Experimental and theoretical elucidation of mechanism of action" in Journal of Inorganic Biochemistry, 205 (2020):110990,
https://doi.org/10.1016/j.jinorgbio.2019.110990 . .