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 . .

TY  - JOUR
AU  - Vujačić Nikezić, Ana V.
AU  - Janjić, Goran
AU  - Bondžić, Aleksandra M.
AU  - Zarić, Božidarka
AU  - Vasic-Anicijevic, Dragana D.
AU  - Momic, Tatjana G.
AU  - Vasić, Vesna M.
PY  - 2018
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2452
AB  - The present paper deals with investigation of the interaction between selected simple structure Au(iii) ([AuCl4](-), [AuCl2(dmso)(2)](+), [AuCl2(bipy)](+)) and Pt(ii) ([PtCl2(dmso)(2)]) complexes with Na/K-ATPase as the target enzyme, using an experimental and theoretical approach. Reaction stoichiometries and binding constants for these enzyme/complex systems were determined, while kinetic measurements were used in order to reveal the type of inhibition. Based on the results obtained by quantum mechanical calculations (electrostatic surface potential (ESP), volume and surface of the complexes) the nature of the investigated complexes was characterized. By using the solvent accessible surface area (SASA) applied on specific inhibitory sites (ion channel and intracellular domains) the nature of these sites was described. Docking studies were used to determine the theoretical probability of the non-covalent metal binding site positions. Inhibition studies implied that all the investigated complexes decreased the activity of the enzyme while the kinetic analysis indicated an uncompetitive mode of inhibition for the selected complexes. Docking results suggested that the main inhibitory site of all these complexes is located in the ion translocation pathway on the extracellular side in the E2P enzyme conformation, similar to the case of cardiac glycosides, specific Na/K-ATPase inhibitors. Also, based on our knowledge, the hydrolyzed forms of [AuCl4](-) and [PtCl2(dmso)(2)] complexes were investigated for the first time by theoretical calculations in this paper. Thereby, a new inhibitory site situated between the M2 and M4 helices was revealed. Binding in this site induces conformational changes in the enzyme domains and perturbs the E1-E2P conformational equilibrium, causing enzyme inhibition.
PB  - Royal Soc Chemistry, Cambridge
T2  - Metallomics
T1  - Interaction of Au(iii) and Pt(ii) complexes with Na/K-ATPase: experimental and theoretical study of reaction stoichiometry and binding sites
VL  - 10
IS  - 7
SP  - 1003
EP  - 1015
DO  - 10.1039/c8mt00111a
ER  - 

@article{
author = "Vujačić Nikezić, Ana V. and Janjić, Goran and Bondžić, Aleksandra M. and Zarić, Božidarka and Vasic-Anicijevic, Dragana D. and Momic, Tatjana G. and Vasić, Vesna M.",
year = "2018",
abstract = "The present paper deals with investigation of the interaction between selected simple structure Au(iii) ([AuCl4](-), [AuCl2(dmso)(2)](+), [AuCl2(bipy)](+)) and Pt(ii) ([PtCl2(dmso)(2)]) complexes with Na/K-ATPase as the target enzyme, using an experimental and theoretical approach. Reaction stoichiometries and binding constants for these enzyme/complex systems were determined, while kinetic measurements were used in order to reveal the type of inhibition. Based on the results obtained by quantum mechanical calculations (electrostatic surface potential (ESP), volume and surface of the complexes) the nature of the investigated complexes was characterized. By using the solvent accessible surface area (SASA) applied on specific inhibitory sites (ion channel and intracellular domains) the nature of these sites was described. Docking studies were used to determine the theoretical probability of the non-covalent metal binding site positions. Inhibition studies implied that all the investigated complexes decreased the activity of the enzyme while the kinetic analysis indicated an uncompetitive mode of inhibition for the selected complexes. Docking results suggested that the main inhibitory site of all these complexes is located in the ion translocation pathway on the extracellular side in the E2P enzyme conformation, similar to the case of cardiac glycosides, specific Na/K-ATPase inhibitors. Also, based on our knowledge, the hydrolyzed forms of [AuCl4](-) and [PtCl2(dmso)(2)] complexes were investigated for the first time by theoretical calculations in this paper. Thereby, a new inhibitory site situated between the M2 and M4 helices was revealed. Binding in this site induces conformational changes in the enzyme domains and perturbs the E1-E2P conformational equilibrium, causing enzyme inhibition.",
publisher = "Royal Soc Chemistry, Cambridge",
journal = "Metallomics",
title = "Interaction of Au(iii) and Pt(ii) complexes with Na/K-ATPase: experimental and theoretical study of reaction stoichiometry and binding sites",
volume = "10",
number = "7",
pages = "1003-1015",
doi = "10.1039/c8mt00111a"
}

Vujačić Nikezić, A. V., Janjić, G., Bondžić, A. M., Zarić, B., Vasic-Anicijevic, D. D., Momic, T. G.,& Vasić, V. M.. (2018). Interaction of Au(iii) and Pt(ii) complexes with Na/K-ATPase: experimental and theoretical study of reaction stoichiometry and binding sites. in Metallomics
Royal Soc Chemistry, Cambridge., 10(7), 1003-1015.
https://doi.org/10.1039/c8mt00111a

Vujačić Nikezić AV, Janjić G, Bondžić AM, Zarić B, Vasic-Anicijevic DD, Momic TG, Vasić VM. Interaction of Au(iii) and Pt(ii) complexes with Na/K-ATPase: experimental and theoretical study of reaction stoichiometry and binding sites. in Metallomics. 2018;10(7):1003-1015.
doi:10.1039/c8mt00111a .

Vujačić Nikezić, Ana V., Janjić, Goran, Bondžić, Aleksandra M., Zarić, Božidarka, Vasic-Anicijevic, Dragana D., Momic, Tatjana G., Vasić, Vesna M., "Interaction of Au(iii) and Pt(ii) complexes with Na/K-ATPase: experimental and theoretical study of reaction stoichiometry and binding sites" in Metallomics, 10, no. 7 (2018):1003-1015,
https://doi.org/10.1039/c8mt00111a . .

TY  - JOUR
AU  - Vujačić, Ana V.
AU  - Savić, J.Z.
AU  - Sovilj, Sofija P.
AU  - Mészáros, Szécsényi K.
AU  - Todorović, Nina
AU  - Petković, M.Z.
AU  - Vasić, Vesna M.
PY  - 2009
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/601
AB  - The kinetics of the reaction between the tetrachloroaurate(III) ion and l-methionine (l-Met) (0.1 M HClO4, pH 1.0-2.5) have been studied spectrophotometrically using a stopped-flow technique at different temperatures. Initially, the fast substitution reaction was ascribed to the formation of the short-lived square-planar Au(III)-(l-Met) that was followed by the replacement of a Cl- ligand and a subsequent, slower reduction to Au(I)-(l-Met). This is an intermolecular process, involving attack on the [AuCl4]- complex by an outer-sphere l-methionine. The activation parameters (ΔH≠ and ΔS≠) for substitution and reduction were determined. IR spectroscopy indicates that l-methionine acts as a bidentate ligand, most likely coordinating via the S and N atoms, while 1H and 13C NMR data indicate methionine sulfoxide as the final product. Finally, the components of the reaction were treated thermally in order to investigate the solid phase synthesis of the resulting complex.
PB  - Oxford : Pergamon-Elsevier Science Ltd
T2  - Polyhedron
T1  - Mechanism of complex formation between [AuCl4]- and l-methionine
VL  - 28
IS  - 3
SP  - 593
EP  - 599
DO  - 10.1016/j.poly.2008.11.045
ER  - 

@article{
author = "Vujačić, Ana V. and Savić, J.Z. and Sovilj, Sofija P. and Mészáros, Szécsényi K. and Todorović, Nina and Petković, M.Z. and Vasić, Vesna M.",
year = "2009",
abstract = "The kinetics of the reaction between the tetrachloroaurate(III) ion and l-methionine (l-Met) (0.1 M HClO4, pH 1.0-2.5) have been studied spectrophotometrically using a stopped-flow technique at different temperatures. Initially, the fast substitution reaction was ascribed to the formation of the short-lived square-planar Au(III)-(l-Met) that was followed by the replacement of a Cl- ligand and a subsequent, slower reduction to Au(I)-(l-Met). This is an intermolecular process, involving attack on the [AuCl4]- complex by an outer-sphere l-methionine. The activation parameters (ΔH≠ and ΔS≠) for substitution and reduction were determined. IR spectroscopy indicates that l-methionine acts as a bidentate ligand, most likely coordinating via the S and N atoms, while 1H and 13C NMR data indicate methionine sulfoxide as the final product. Finally, the components of the reaction were treated thermally in order to investigate the solid phase synthesis of the resulting complex.",
publisher = "Oxford : Pergamon-Elsevier Science Ltd",
journal = "Polyhedron",
title = "Mechanism of complex formation between [AuCl4]- and l-methionine",
volume = "28",
number = "3",
pages = "593-599",
doi = "10.1016/j.poly.2008.11.045"
}

Vujačić, A. V., Savić, J.Z., Sovilj, S. P., Mészáros, S. K., Todorović, N., Petković, M.Z.,& Vasić, V. M.. (2009). Mechanism of complex formation between [AuCl4]- and l-methionine. in Polyhedron
Oxford : Pergamon-Elsevier Science Ltd., 28(3), 593-599.
https://doi.org/10.1016/j.poly.2008.11.045

Vujačić AV, Savić J, Sovilj SP, Mészáros SK, Todorović N, Petković M, Vasić VM. Mechanism of complex formation between [AuCl4]- and l-methionine. in Polyhedron. 2009;28(3):593-599.
doi:10.1016/j.poly.2008.11.045 .

Vujačić, Ana V., Savić, J.Z., Sovilj, Sofija P., Mészáros, Szécsényi K., Todorović, Nina, Petković, M.Z., Vasić, Vesna M., "Mechanism of complex formation between [AuCl4]- and l-methionine" in Polyhedron, 28, no. 3 (2009):593-599,
https://doi.org/10.1016/j.poly.2008.11.045 . .