Aminoalcoholate-driven tetracopper(II) cores as dual acetyl and butyrylcholinesterase inhibitors: Experimental and theoretical elucidation of mechanism of action
Само за регистроване кориснике
2020
Аутори
Bondžić, AleksandraSenćanski, Milan
Vujačić Nikezić, Ana V.
Kirillova, Marina V.
André, Vânia
Kirillov, Alexander M.
Bondžić, Bojan
Чланак у часопису (Објављена верзија)
,
Elsevier
Метаподаци
Приказ свих података о документуАпстракт
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.
Кључне речи:
AChE / BuChE / Dual inhibitors / Docking studiesИзвор:
Journal of Inorganic Biochemistry, 2020, 205, 110990-Издавач:
- Elsevier
Финансирање / пројекти:
- Истраживања интеракција ензима са токсичним и фармаколошки активним молекулима (RS-172023)
- Примена EIIP/ISM биоинформатичке платформе у откривању нових терапеутских таргета и потенцијалних терапеутских молекула (RS-173001)
- Експериментална и теоријска проучавања реактивности и биолошка активност стереодефинисаних тиазолидина и синтетичких аналога (RS-172020)
- Foundation for Science and Technology (FCT) and Portugal 2020 (projects LISBOA-01-0145- FEDER-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 5-100
- EU COST Action CA15135 (MuTaLig)
- EU COST Action CA15106 (CHAOS)
DOI: 10.1016/j.jinorgbio.2019.110990
ISSN: 0162-0134
PubMed: 32035286
WoS: 000522119300020
Scopus: 2-s2.0-85078834022
Институција/група
IHTMTY - 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 . .