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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

General Research Article

Computational and Kinetic Studies of Acetylcholine Esterase Inhibition by Phenserine

Author(s): Shams Tabrez* and Ghazi A. Damanhouri

Volume 25 , Issue 18 , 2019

Page: [2108 - 2112] Pages: 5

DOI: 10.2174/1381612825666190618141015

Price: $65


Background: The inhibition of cholinesterase enzymes is one of the promising strategies to manage several neurological disorders that include Alzheimer's disease (AD).

Material and Methods: In the current article, we estimated the potential inhibition of acetyl cholinesterase (AChE) by phenserine using slightly modified Ellman assay. To find out the binding interactions of phenserine with the catalytic site of AChE, a molecular docking study was also performed.

Results: Phenserine was found to inhibit Electrophorus electricus AChE in a dose-dependent manner with an IC50 value of 0.013 µM. The kinetic analyses indicate that phenserine inhibits AChE in a mixed type manner (competitive and uncompetitive) with Ki values of 0.39 μmole/l and 0.21 µmole/l, respectively. On the other hand, Km and Vmax values were found to be 0.17 µM and 0.39 µM, respectively. The molecular docking studies indicate efficient binding of phenserine through 6 hydrogen bonds, 4 pi-alkyl interactions, and 1 pi-pi interaction within the AChE catalytic pocket.

Conclusion: Results of our computational and kinetics studies indicated a mixed type inhibition by phenserine at AChE catalytic site.

Keywords: Acetylcholine esterase, inhibition, kinetics, molecular docking, phenserine, cholinesterase enzymes.

Brown RC, Lockwood AH, Sonawane BR. Neurodegenerative diseases: An overview of environmental risk factors. Environ Health Perspect 2005; 113(9): 1250-6.
[] [PMID: 16140637]
Islam BU, Zaidi SK, Kamal MA, Tabrez S. Exploration of various proteins for the treatment of Alzheimer’s disease. Curr Drug Metab 2017; 18(9): 808-13.
[] [PMID: 28164752]
Jabir NR, Firoz CK, Baeesa SS, et al. Synopsis on the linkage of Alzheimer’s and Parkinson’s disease with chronic diseases. CNS Neurosci Ther 2015; 21(1): 1-7.
[] [PMID: 25399848]
Jabir NR, Khan FR, Tabrez S. Cholinesterase targeting by polyphenols: A therapeutic approach for the treatment of Alzheimer’s disease. CNS Neurosci Ther 2018; 24(9): 753-62.
[] [PMID: 29770579]
Islam BU, Tabrez S. Management of Alzheimer’s disease-An insight of the enzymatic and other novel potential targets. Int J Biol Macromol 2017; 97: 700-9.
[] [PMID: 28111296]
Rizvi SMD, Shaikh S, Naaz D, et al. Kinetics and molecular docking study of an anti-diabetic drug glimepiride as acetylcholinesterase inhibitor: Implication for Alzheimer’s disease-diabetes dual therapy. Neurochem Res 2016; 41(6): 1475-82.
[] [PMID: 26886763]
Islam BU, Khan M, Jabir N, Kamal M, Tabrez S. Elucidating treatment of Alzheimer’s disease via different receptors. Curr Top Med Chem 2017; 17: 1400-7.
[] [PMID: 28049400]
Yu Q-S, Reale M, Kamal MA, et al. Synthesis of the Alzheimer drug Posiphen into its primary metabolic products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their inhibition of amyloid precursor protein, α-Synuclein synthesis, interleukin-1β release, and cholinergic action. Antiinflamm Antiallergy Agents Med Chem 2013; 12(2): 117-28.
[] [PMID: 23360256]
Thatte U. Phenserine axonyx. Curr Opin Investig Drugs 2005; 6: 729-39.
Winblad B, Giacobini E, Frölich L, et al. Phenserine efficacy in Alzheimer’s disease. J Alzheimers Dis 2010; 22(4): 1201-8.
[] [PMID: 20930279]
Araujo JA, Greig NH, Ingram DK, Sandin J, de Rivera C, Milgram NW. Cholinesterase inhibitors improve both memory and complex learning in aged beagle dogs. J Alzheimers Dis 2011; 26(1): 143-55.
[] [PMID: 21593569]
Chen J, Pan H, Chen C, et al. (-)-Phenserine attenuates soman-induced neuropathology. PLoS One 2014; 9(6): e99818.
[] [PMID: 24955574]
Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30(16): 2785-91.
[] [PMID: 19399780]
Rizvi SMD, Shakil S, Haneef M. A simple click by click protocol to perform docking: AutoDock 4.2 made easy for non-bioinformaticians. EXCLI J 2013; 12: 831-57.
[PMID: 26648810]
Komersová A, Komers K, Cegan A. New findings about Ellman’s method to determine cholinesterase activity. Z Natforsch C J Biosci 2007; 62(1-2): 150-4.
[] [PMID: 17425121]
Askar KA, Kudi AC, Moody AJ. Comparative analysis of cholinesterase activities in food animals using modified Ellman and Michel assays. Can J Vet Res 2011; 75(4): 261-70.
[PMID: 22468023]
Shakil S, Khan R, Tabrez S, et al. Interaction of human brain acetylcholinesterase with cyclophosphamide: a molecular modeling and docking study. CNS Neurol Disord Drug Targets 2011; 10(7): 845-8.
[] [PMID: 21999734]
Shakil S. Molecular Interaction of Anti-Diabetic Drugs With Acetylcholinesterase and Sodium Glucose Co-Transporter 2. J Cell Biochem 2017; 118(11): 3855-65.
[] [PMID: 28387957]
Lilja AM, Luo Y, Yu QS, et al. Neurotrophic and neuroprotective actions of (-)- and (+)-phenserine, candidate drugs for Alzheimer’s disease. PLoS One 2013; 8(1): e54887.
[] [PMID: 23382994]
Maccecchini ML, Chang MY, Pan C, John V, Zetterberg H, Greig NH. Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans. J Neurol Neurosurg Psychiatry 2012; 83(9): 894-902.
[] [PMID: 22791904]
Mikkilineni S, Cantuti-Castelvetri I, Cahill CM, Balliedier A, Greig NH, Rogers JT. The anticholinesterase phenserine and its enantiomer posiphen as 5′untranslated-region-directed translation blockers of the parkinson’s alpha synuclein expression. Parkinsons Dis 2012; 2012: 142372.
[] [PMID: 22693681]
Lahiri DK, Chen D, Maloney B, et al. The experimental Alzheimer’s disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice. J Pharmacol Exp Ther 2007; 320(1): 386-96.
[] [PMID: 17003227]
Teich AF, Sharma E, Barnwell E, et al. Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse. Alzheimers Dement (N Y) 2018; 4: 37-45.
[] [PMID: 29955650]

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