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1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone as a potent transition-state analogue slow-binding inhibitor of human acetylcholinesterase: Kinetic, MD and QM/MM studies

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dc.contributor.author Zueva I.V.
dc.contributor.author Lushchekina S.V.
dc.contributor.author Pottie I.R.
dc.contributor.author Darvesh S.
dc.contributor.author Masson P.
dc.date.accessioned 2021-02-25T20:52:44Z
dc.date.available 2021-02-25T20:52:44Z
dc.date.issued 2020
dc.identifier.uri https://dspace.kpfu.ru/xmlui/handle/net/162564
dc.description.abstract © 2020 by the authors. Licensee MDPI, Basel, Switzerland. Kinetic studies and molecular modeling of human acetylcholinesterase (AChE) inhibition by a fluorinated acetophenone derivative, 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (TFK), were performed. Fast reversible inhibition of AChE by TFK is of competitive type with Ki = 5.15 nM. However, steady state of inhibition is reached slowly. Kinetic analysis showed that TFK is a slow-binding inhibitor (SBI) of type B with Ki * = 0.53 nM. Reversible binding of TFK provides a long residence time, τ = 20 min, on AChE. After binding, TFK acylates the active serine, forming an hemiketal. Then, disruption of hemiketal (deacylation) is slow. AChE recovers full activity in approximately 40 min. Molecular docking and MD simulations depicted the different steps. It was shown that TFK binds first to the peripheral anionic site. Then, subsequent slow induced-fit step enlarged the gorge, allowing tight adjustment into the catalytic active site. Modeling of interactions between TFK and AChE active site by QM/MM showed that the “isomerization” step of enzyme-inhibitor complex leads to a complex similar to substrate tetrahedral intermediate, a so-called “transition state analog”, followed by a labile covalent intermediate. SBIs of AChE show prolonged pharmacological efficacy. Thus, this fluoroalkylketone intended for neuroimaging, could be of interest in palliative therapy of Alzheimer’s disease and protection of central AChE against organophosphorus compounds.
dc.subject Acetylcholinesterase
dc.subject Organophosphorus
dc.subject Slow-binding inhibition
dc.subject Transition state analog
dc.title 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone as a potent transition-state analogue slow-binding inhibitor of human acetylcholinesterase: Kinetic, MD and QM/MM studies
dc.type Article
dc.relation.ispartofseries-issue 12
dc.relation.ispartofseries-volume 10
dc.collection Публикации сотрудников КФУ
dc.relation.startpage 1
dc.source.id SCOPUS-2020-10-12-SID85097037780


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  • Публикации сотрудников КФУ Scopus [24551]
    Коллекция содержит публикации сотрудников Казанского федерального (до 2010 года Казанского государственного) университета, проиндексированные в БД Scopus, начиная с 1970г.

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