Publication Type Journal Article
Title Aminoalcoholate-driven tetracopper(II) cores as dual acetyl and butyrylcholinesterase inhibitors: Experimental and theoretical elucidation of mechanism of action
Authors Aleksandra M. Bondzic V Sencanski Ana V. Vujacic Nikezic V Kirillova Vânia André A Kirillov Bojan P. Bondzic
Groups BioMol
Journal JOURNAL OF INORGANIC BIOCHEMISTRY
Year 2020
Month April
Volume 205
Number
Pages
Abstract Three coordination compounds featuring different types of tetracopper(II) cores, namely [O subset of Cu-4\N(CH2CH2O)(3)\(4)(BOH)(4)][BF4](2) (1), [Cu-4(mu(4)-H(2)edte)(mu(5)-H(2)edte)(sal)(2)](n)center dot 7nH(2)O, (H(4)edte = N,N,N , N -tetrakis(2-hydroxyethyl)ethylenediamine, H(2)sal = salicylic acid) (2), and [\Cu4(mu(3)-Hbes)(4)(mu-hba)\K(H2O)(3)](n) H(3)bes = 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, V(max )and K-m 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 K i 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.
DOI http://dx.doi.org/10.1016/j.jinorgbio.2019.110990
ISBN
Publisher
Book Title
ISSN 0162-0134
EISSN 1873-3344
Conference Name
Bibtex ID ISI:000522119300020
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