A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules - the role in the mechanism of AChE inhibition.

Autor: Bondžić AM; Department of Physical Chemistry, 'VINČA' Institute of Nuclear Sciences- National Institute of thе Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia. Electronic address: aleksandrab@vin.bg.ac.rs., Lazarević-Pašti TD; Department of Physical Chemistry, 'VINČA' Institute of Nuclear Sciences- National Institute of thе Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia., Leskovac AR; Department of Physical Chemistry, 'VINČA' Institute of Nuclear Sciences- National Institute of thе Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia., Petrović SŽ; Department of Physical Chemistry, 'VINČA' Institute of Nuclear Sciences- National Institute of thе Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia., Čolović MB; Department of Physical Chemistry, 'VINČA' Institute of Nuclear Sciences- National Institute of thе Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia., Parac-Vogt TN; Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium., Janjić GV; Institute of Chemistry, Technology and Metallurgy, National Institute, University of Belgrade, Njegoševa 12, Belgrade, Serbia. Electronic address: goran.janjic@ihtm.bg.ac.rs.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2020 Aug 01; Vol. 151, pp. 105376. Date of Electronic Publication: 2020 May 31.
DOI: 10.1016/j.ejps.2020.105376
Abstrakt: Acetylcholinesterase (AChE) inhibitors are important in the treatment of neurodegenerative diseases. Two inhibitors, 12-tungstosilicic acid (WSiA) and 12-tungstophosphoric acid (WPA), which have polyoxometalate (POM) type structure, have been shown to inhibit AChE activity in nM concentration. Circular dichroism and tryptophan fluorescence spectroscopy demonstrated that the AChE inhibition was not accompanied by significant changes in the secondary structure of the enzyme. The molecular docking approach has revealed a new allosteric binding site, termed β-allosteric site (β-AS), which is considered responsible for the inhibition of AChE by POMs. To the best of our knowledge, this is the first study reporting a new allosteric site that is considered responsible for AChE inhibition by voluminous and negatively charged molecules such as POMs. The selected POMs were further subjected to genotoxicity testing using human peripheral blood cells as a model system. It was shown that WSiA and WPA induced a mild cytostatic but not genotoxic effects in human lymphocytes, which indicates their potential to be used as medicinal drugs. The identification of non-toxic compounds capable of binding to an allosteric site that so far has not been considered responsible for enzyme inhibition could be fundamental for the development of new drug design strategies and the discovery of more efficient AChE modulators.
Competing Interests: Declaration Competing of Interest None.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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