Acetylcholinesterase Choline-Based Ionic Liquid Inhibitors: In Vitro and in Silico Molecular Docking Studies

Filipa Siopa, Raquel F. M. Frade, Ana Diniz, Joana M. Andrade, Marisa Nicolai, Ana Meirinhos, Susana D. Lucas, Filipa Marcelo, Carlos A. M. Afonso, Patrícia Rijo

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Abstract

Monocationic and dicationic cholinium ionic liquids (ILs) were synthesized and evaluated as acetylcholinesterase (AChE) inhibitors with in vitro and in silico models, and their cytotoxicity was assessed using human cell lines from skin (CRL-1502) and colon cancer (CaCo-2). The ILs with a longer alkyl chain were stronger AChE inhibitors, the dicationic ILs (DILs) being more active than the monocationic ILs. The best result was obtained for [N1,1,12,2(OH)]2Br2 at a concentration of 0.18 μM by reducing half enzyme activity without affecting the viability of tested cell lines. A saturation-transfer difference NMR (STD-NMR) binding study was carried out, demonstrating that [N1,1,12,2(OH)]2Br2 binds to AChE. STD-NMR competition binding experiments, using galanthamine as a reference ligand, clearly highlight that the IL displaces galanthamine in the AChE binding site pinpointing [N1,1,12,2(OH)]2Br2 inside the deep gorge of AChE. In order to obtain a three-dimensional (3D) view of the molecular recognition process, in silico molecular docking studies on the active site of AChE were carried out. The proposed 3D model of the AChE/DIL complex is in agreement with the STD-derived epitope mapping, which explains the competition with galanthamine and unveils key interactions in both peripheral and catalytic sites of AChE. These interactions seem essential to govern the recognition of DILs by the AChE enzyme. Our study provides a structural and functional platform that can be used for the rational design of choline-based ILs as potent AChE inhibitors.

Original languageEnglish
Pages (from-to)17145-17154
Number of pages10
JournalACS Omega
Volume3
Issue number12
DOIs
Publication statusPublished - 12 Dec 2018

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Ionic Liquids
Acetylcholinesterase
Choline
Ionic liquids
Galantamine
Cholinesterase Inhibitors
Cells
Nuclear magnetic resonance
Epitopes
Molecular recognition
Enzyme activity
Binding sites
Cytotoxicity
Skin
Enzymes
Ligands
Binding Sites

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Siopa, F., Frade, R. F. M., Diniz, A., Andrade, J. M., Nicolai, M., Meirinhos, A., ... Rijo, P. (2018). Acetylcholinesterase Choline-Based Ionic Liquid Inhibitors: In Vitro and in Silico Molecular Docking Studies. ACS Omega, 3(12), 17145-17154. https://doi.org/10.1021/acsomega.8b02347
Siopa, Filipa ; Frade, Raquel F. M. ; Diniz, Ana ; Andrade, Joana M. ; Nicolai, Marisa ; Meirinhos, Ana ; Lucas, Susana D. ; Marcelo, Filipa ; Afonso, Carlos A. M. ; Rijo, Patrícia. / Acetylcholinesterase Choline-Based Ionic Liquid Inhibitors: In Vitro and in Silico Molecular Docking Studies. In: ACS Omega. 2018 ; Vol. 3, No. 12. pp. 17145-17154.
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Siopa, F, Frade, RFM, Diniz, A, Andrade, JM, Nicolai, M, Meirinhos, A, Lucas, SD, Marcelo, F, Afonso, CAM & Rijo, P 2018, 'Acetylcholinesterase Choline-Based Ionic Liquid Inhibitors: In Vitro and in Silico Molecular Docking Studies', ACS Omega, vol. 3, no. 12, pp. 17145-17154. https://doi.org/10.1021/acsomega.8b02347

Acetylcholinesterase Choline-Based Ionic Liquid Inhibitors: In Vitro and in Silico Molecular Docking Studies. / Siopa, Filipa; Frade, Raquel F. M.; Diniz, Ana; Andrade, Joana M.; Nicolai, Marisa; Meirinhos, Ana; Lucas, Susana D.; Marcelo, Filipa; Afonso, Carlos A. M.; Rijo, Patrícia.

In: ACS Omega, Vol. 3, No. 12, 12.12.2018, p. 17145-17154.

Research output: Contribution to journalArticle

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T1 - Acetylcholinesterase Choline-Based Ionic Liquid Inhibitors: In Vitro and in Silico Molecular Docking Studies

AU - Siopa, Filipa

AU - Frade, Raquel F. M.

AU - Diniz, Ana

AU - Andrade, Joana M.

AU - Nicolai, Marisa

AU - Meirinhos, Ana

AU - Lucas, Susana D.

AU - Marcelo, Filipa

AU - Afonso, Carlos A. M.

AU - Rijo, Patrícia

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N2 - Monocationic and dicationic cholinium ionic liquids (ILs) were synthesized and evaluated as acetylcholinesterase (AChE) inhibitors with in vitro and in silico models, and their cytotoxicity was assessed using human cell lines from skin (CRL-1502) and colon cancer (CaCo-2). The ILs with a longer alkyl chain were stronger AChE inhibitors, the dicationic ILs (DILs) being more active than the monocationic ILs. The best result was obtained for [N1,1,12,2(OH)]2Br2 at a concentration of 0.18 μM by reducing half enzyme activity without affecting the viability of tested cell lines. A saturation-transfer difference NMR (STD-NMR) binding study was carried out, demonstrating that [N1,1,12,2(OH)]2Br2 binds to AChE. STD-NMR competition binding experiments, using galanthamine as a reference ligand, clearly highlight that the IL displaces galanthamine in the AChE binding site pinpointing [N1,1,12,2(OH)]2Br2 inside the deep gorge of AChE. In order to obtain a three-dimensional (3D) view of the molecular recognition process, in silico molecular docking studies on the active site of AChE were carried out. The proposed 3D model of the AChE/DIL complex is in agreement with the STD-derived epitope mapping, which explains the competition with galanthamine and unveils key interactions in both peripheral and catalytic sites of AChE. These interactions seem essential to govern the recognition of DILs by the AChE enzyme. Our study provides a structural and functional platform that can be used for the rational design of choline-based ILs as potent AChE inhibitors.

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