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Aminoalcoholate-driven tetracopper(II) cores as dual acetyl and butyrylcholinesterase inhibitors: Experimental and theoretical elucidation of mechanism of action
dc.creator | Bondžić, Aleksandra | |
dc.creator | Senćanski, Milan | |
dc.creator | Vujačić Nikezić, Ana V. | |
dc.creator | Kirillova, Marina V. | |
dc.creator | André, Vânia | |
dc.creator | Kirillov, Alexander M. | |
dc.creator | Bondžić, Bojan | |
dc.date.accessioned | 2020-12-03T12:15:04Z | |
dc.date.available | 2020-12-03T12:15:04Z | |
dc.date.issued | 2020 | |
dc.identifier.issn | 0162-0134 | |
dc.identifier.uri | https://cer.ihtm.bg.ac.rs/handle/123456789/3958 | |
dc.description.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. | en |
dc.language.iso | en | sr |
dc.publisher | Elsevier | sr |
dc.relation | info:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172023/RS// | sr |
dc.relation | info:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173001/RS// | sr |
dc.relation | info:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172020/RS// | sr |
dc.relation | Foundation for Science and Technology (FCT) and Portugal 2020 (projects LISBOA-01-0145- FEDER-029697) | sr |
dc.relation | Foundation for Science and Technology (FCT) and Portugal 2020 ( IF/01395/2013/CP1163/CT005) | sr |
dc.relation | Foundation for Science and Technology (FCT) and Portugal 2020 (CEECIND/03708/ 2017) | sr |
dc.relation | Foundation for Science and Technology (FCT) and Portugal 2020 (UIDB/00100/2020) | sr |
dc.relation | Foundation for Science and Technology (FCT) and Portugal 2020 (SFRH/BSAB/150368) | sr |
dc.relation | RUDN University Program 5-100 | sr |
dc.relation | EU COST Action CA15135 (MuTaLig) | sr |
dc.relation | EU COST Action CA15106 (CHAOS) | sr |
dc.rights | restrictedAccess | sr |
dc.source | Journal of Inorganic Biochemistry | sr |
dc.subject | AChE | sr |
dc.subject | BuChE | sr |
dc.subject | Dual inhibitors | sr |
dc.subject | Docking studies | sr |
dc.title | Aminoalcoholate-driven tetracopper(II) cores as dual acetyl and butyrylcholinesterase inhibitors: Experimental and theoretical elucidation of mechanism of action | en |
dc.type | article | sr |
dc.rights.license | ARR | sr |
dcterms.abstract | Бонджић, Бојан; Бонджић, Aлександра; Сенћански, Милан В.; Кириллов, Aлеxандер М.; Aндрé, Вâниа; Вујачић Никезић, Aна В.; Кириллова, Марина В.; | |
dc.rights.holder | Elsevier | sr |
dc.citation.volume | 205 | |
dc.citation.spage | 110990 | |
dc.citation.rank | M21~ | |
dc.identifier.pmid | 32035286 | |
dc.identifier.doi | 10.1016/j.jinorgbio.2019.110990 | |
dc.identifier.scopus | 2-s2.0-85078834022 | |
dc.identifier.wos | 000522119300020 | |
dc.type.version | publishedVersion | sr |