Aminoalcoholate-driven tetracopper(II) cores as dual acetyl and butyrylcholinesterase inhibitors: Experimental and theoretical elucidation of mechanism of action
Authorized Users Only
2020
Authors
Bondžić, Aleksandra M.Senćanski, Milan V.
Vujačić Nikezić, Ana V.
Kirillova, Marina V.
André, Vania
Kirillov, Alexander M.
Bondžić, Bojan P.
Article (Published version)
,
© 2020 Elsevier Inc.
Metadata
Show full item recordAbstract
Three coordination compounds featuring different types of tetracopper(II) cores, namely [O ⊂ Cu4N(CH2CH2O)34(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. © 2020 Elsevier Inc.
Keywords:
AChE / BuChE / Dual inhibitors / Docking studiesSource:
Journal of Inorganic Biochemistry, 2020, 205, 110990-Funding / projects:
- Studies of enzyme interactions with toxic and pharmacologically active molecules (RS-MESTD-Basic Research (BR or ON)-172023)
- Application of the EIIP/ISM bioinformatics platform in discovery of novel therapeutic targets and potential therapeutic molecules (RS-MESTD-Basic Research (BR or ON)-173001)
- Experimental and theoretical study of reactivity and biological activity of stereodefined thiazolidines and their synthetic analogues (RS-MESTD-Basic Research (BR or ON)-172020)
- Foundation for Science and Technology (FCT) and Portugal 2020 [LISBOA-01-0145FEDER-029697]
- Foundation for Science and Technology (FCT) and Portugal 2020 [IF/01395/2013/CP1163/CT005]
- Foundation for Science and Technology (FCT) and Portugal 2020 [CEECIND/03708/2017]
- Foundation for Science and Technology (FCT) and Portugal 2020 [UIDB/00100/2020]
- Foundation for Science and Technology (FCT) and Portugal 2020 [SFRH/BSAB/150368]
- RUDN University Program 5100
- COST Action [CA15135 - MuTaLig]
- COST Action [CA15106 - CHAOS]
DOI: 10.1016/j.jinorgbio.2019.110990
ISSN: 0162-0134
PubMed: 32035286
WoS: 000522119300020
Scopus: 2-s2.0-85078834022
Collections
Institution/Community
VinčaTY - JOUR AU - Bondžić, Aleksandra M. AU - Senćanski, Milan V. AU - Vujačić Nikezić, Ana V. AU - Kirillova, Marina V. AU - André, Vania AU - Kirillov, Alexander M. AU - Bondžić, Bojan P. PY - 2020 UR - https://vinar.vin.bg.ac.rs/handle/123456789/8806 AB - Three coordination compounds featuring different types of tetracopper(II) cores, namely [O ⊂ Cu4N(CH2CH2O)34(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. © 2020 Elsevier Inc. 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 M. and Senćanski, Milan V. and Vujačić Nikezić, Ana V. and Kirillova, Marina V. and André, Vania and Kirillov, Alexander M. and Bondžić, Bojan P.", year = "2020", abstract = "Three coordination compounds featuring different types of tetracopper(II) cores, namely [O ⊂ Cu4N(CH2CH2O)34(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. © 2020 Elsevier Inc.", 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. M., Senćanski, M. V., Vujačić Nikezić, A. V., Kirillova, M. V., André, V., Kirillov, A. M.,& Bondžić, B. P.. (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, 205, 110990. https://doi.org/10.1016/j.jinorgbio.2019.110990
Bondžić AM, Senćanski MV, Vujačić Nikezić AV, Kirillova MV, André V, Kirillov AM, Bondžić BP. 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 M., Senćanski, Milan V., Vujačić Nikezić, Ana V., Kirillova, Marina V., André, Vania, Kirillov, Alexander M., Bondžić, Bojan P., "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 . .