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Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE-ligand interactions by docking calculations and molecular dynamics simulations

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2014
j.ejmech.2014.05.008.pdf (5.862Mb)
Аутори
Vitorović-Todorović, Maja D.
Koukoulitsa, Catherine
Juranić, Ivan
Mandić, Ljuba M.
Drakulić, Branko
Чланак у часопису (Рецензирана верзија)
Метаподаци
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Апстракт
Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, synthesized and evaluated for acetyl- and butyrylcholinesterase inhibitory activity. Structural variations included cycloalkylamino group attached to C2 position of butanoyl moiety, and variation of amido moiety of molecules. Twelve compounds, mostly piperidino and imidazolo derivatives, inhibited AChE in low micromolar range, and were inactive toward BChE. Several N-methylpiperazino derivatives showed inhibition of BChE in low micromolar or submicromolar concentrations, and were inactive toward AChE. Therefore, the nature of the cycloalkylamino moiety governs the AChE/BChE selectivity profile of compounds. The most active AChE inhibitor showed mixed-type inhibition modality, indicating its binding to free enzyme and to enzyme-substrate complex. Thorough docking calculations of the seven most potent AChE inhibitors from the set, showed that the hydrogen bond can be formed between amide -NH- ...moiety of compounds and -OH group of Tyr 124. The 10 ns unconstrained molecular dynamic simulation of the AChE- compound 18 complex shows that this interaction is the most persistent. This is, probably, the major anchoring point for the binding. (C) 2014 Elsevier Masson SAS. All rights reserved.

Кључне речи:
4-Aryl-4-oxo-2-aminylbutyramides / Anticholinesterase activity / Mixed type reversible inhibitors / Docking study / Molecular dynamics
Извор:
European Journal of Medicinal Chemistry, 2014, 81, 158-175
Издавач:
  • Elsevier France-Editions Scientifiques Medicales Elsevier, Paris
Финансирање / пројекти:
  • High-Performance Computing Infrastructure for South East Europe's Research Communities (EU-261499)
  • Рационални дизајн и синтеза биолошки активних и координационих једињења и функционалних материјала, релевантних у (био)нанотехнологији (RS-172035)
Напомена:
  • This is the peer-reviewed version of the article: Vitorović-Todorović, M. D.; Koukoulitsa, C.; Juranić, I. O.; Mandić, L. M.; Drakulić, B. J. Structural Modifications of 4-Aryl-4-Oxo-2-Aminylbutanamides and Their Acetyl- and Butyrylcholinesterase Inhibitory Activity. Investigation of AChE-Ligand Interactions by Docking Calculations and Molecular Dynamics Simulations. European Journal of Medicinal Chemistry 2014, 81, 158–175. https://doi.org/10.1016/j.ejmech.2014.05.008
  • http://cer.ihtm.bg.ac.rs/handle/123456789/2688

DOI: 10.1016/j.ejmech.2014.05.008

ISSN: 0223-5234

PubMed: 24836068

WoS: 000338598400015

Scopus: 2-s2.0-84900870587
[ Google Scholar ]
16
16
URI
https://cer.ihtm.bg.ac.rs/handle/123456789/3134
Колекције
  • Radovi istraživača / Researchers' publications
Институција/група
IHTM
TY  - JOUR
AU  - Vitorović-Todorović, Maja D.
AU  - Koukoulitsa, Catherine
AU  - Juranić, Ivan
AU  - Mandić, Ljuba M.
AU  - Drakulić, Branko
PY  - 2014
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/3134
AB  - Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, synthesized and evaluated for acetyl- and butyrylcholinesterase inhibitory activity. Structural variations included cycloalkylamino group attached to C2 position of butanoyl moiety, and variation of amido moiety of molecules. Twelve compounds, mostly piperidino and imidazolo derivatives, inhibited AChE in low micromolar range, and were inactive toward BChE. Several N-methylpiperazino derivatives showed inhibition of BChE in low micromolar or submicromolar concentrations, and were inactive toward AChE. Therefore, the nature of the cycloalkylamino moiety governs the AChE/BChE selectivity profile of compounds. The most active AChE inhibitor showed mixed-type inhibition modality, indicating its binding to free enzyme and to enzyme-substrate complex. Thorough docking calculations of the seven most potent AChE inhibitors from the set, showed that the hydrogen bond can be formed between amide -NH- moiety of compounds and -OH group of Tyr 124. The 10 ns unconstrained molecular dynamic simulation of the AChE- compound 18 complex shows that this interaction is the most persistent. This is, probably, the major anchoring point for the binding. (C) 2014 Elsevier Masson SAS. All rights reserved.
PB  - Elsevier France-Editions Scientifiques Medicales Elsevier, Paris
T2  - European Journal of Medicinal Chemistry
T1  - Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE-ligand interactions by docking calculations and molecular dynamics simulations
VL  - 81
SP  - 158
EP  - 175
DO  - 10.1016/j.ejmech.2014.05.008
ER  - 
@article{
author = "Vitorović-Todorović, Maja D. and Koukoulitsa, Catherine and Juranić, Ivan and Mandić, Ljuba M. and Drakulić, Branko",
year = "2014",
abstract = "Congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides has been designed, synthesized and evaluated for acetyl- and butyrylcholinesterase inhibitory activity. Structural variations included cycloalkylamino group attached to C2 position of butanoyl moiety, and variation of amido moiety of molecules. Twelve compounds, mostly piperidino and imidazolo derivatives, inhibited AChE in low micromolar range, and were inactive toward BChE. Several N-methylpiperazino derivatives showed inhibition of BChE in low micromolar or submicromolar concentrations, and were inactive toward AChE. Therefore, the nature of the cycloalkylamino moiety governs the AChE/BChE selectivity profile of compounds. The most active AChE inhibitor showed mixed-type inhibition modality, indicating its binding to free enzyme and to enzyme-substrate complex. Thorough docking calculations of the seven most potent AChE inhibitors from the set, showed that the hydrogen bond can be formed between amide -NH- moiety of compounds and -OH group of Tyr 124. The 10 ns unconstrained molecular dynamic simulation of the AChE- compound 18 complex shows that this interaction is the most persistent. This is, probably, the major anchoring point for the binding. (C) 2014 Elsevier Masson SAS. All rights reserved.",
publisher = "Elsevier France-Editions Scientifiques Medicales Elsevier, Paris",
journal = "European Journal of Medicinal Chemistry",
title = "Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE-ligand interactions by docking calculations and molecular dynamics simulations",
volume = "81",
pages = "158-175",
doi = "10.1016/j.ejmech.2014.05.008"
}
Vitorović-Todorović, M. D., Koukoulitsa, C., Juranić, I., Mandić, L. M.,& Drakulić, B.. (2014). Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE-ligand interactions by docking calculations and molecular dynamics simulations. in European Journal of Medicinal Chemistry
Elsevier France-Editions Scientifiques Medicales Elsevier, Paris., 81, 158-175.
https://doi.org/10.1016/j.ejmech.2014.05.008
Vitorović-Todorović MD, Koukoulitsa C, Juranić I, Mandić LM, Drakulić B. Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE-ligand interactions by docking calculations and molecular dynamics simulations. in European Journal of Medicinal Chemistry. 2014;81:158-175.
doi:10.1016/j.ejmech.2014.05.008 .
Vitorović-Todorović, Maja D., Koukoulitsa, Catherine, Juranić, Ivan, Mandić, Ljuba M., Drakulić, Branko, "Structural modifications of 4-aryl-4-oxo-2-aminylbutanamides and their acetyl- and butyrylcholinesterase inhibitory activity. Investigation of AChE-ligand interactions by docking calculations and molecular dynamics simulations" in European Journal of Medicinal Chemistry, 81 (2014):158-175,
https://doi.org/10.1016/j.ejmech.2014.05.008 . .

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