Harnessing memantine in Alzheimer's disease therapy through inhibition of microtubule affinity-regulating kinase : Mechanistic insights
Copyright © 2024 Elsevier B.V. All rights reserved..
Alzheimer's disease (AD) is one of the neurodegenerative disorder that primarily affects memory, thinking, and behavior, eventually leading to severe cognitive impairment. Therapeutic management of AD is urgently needed to improve the quality and lifestyle of patients. Tau phosphorylating kinases are considered attractive therapeutic targets. Microtubule affinity-regulating kinase 4 (MARK4) is directly linked with pathological phosphorylations of tau, highlighting its role in the therapeutic targeting of AD. The current manuscript shows the MARK4 inhibitory effect of Memantine (MEM), a drug used in treating AD. We have performed fluorescence based binding measurements, enzyme inhibition assay, docking and molecular dynamics (MD) simulations to understand the binding of of MARK4 and MEM and subsequent inhibition in the kinase activity. A 100 ns MD simulations provided a detailed analysis of MARK4-MEM complex and the role of potential critical residues in the binding. Finally, this study provides molecular insights into the therapeutic implication of MEM in AD therapeutics. We propose MEM effectively inhibits MARK4, it may be implicated in the development of targeted and efficient treatments for AD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:262 |
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| Enthalten in: |
International journal of biological macromolecules - 262(2024), Pt 2 vom: 09. März, Seite 130090 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Anwar, Saleha [VerfasserIn] |
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| Links: |
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| Themen: |
Alzheimer's disease |
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| Anmerkungen: |
Date Completed 27.03.2024 Date Revised 27.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ijbiomac.2024.130090 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368318346 |
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| 245 | 1 | 0 | |a Harnessing memantine in Alzheimer's disease therapy through inhibition of microtubule affinity-regulating kinase |b Mechanistic insights |
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| 500 | |a Date Revised 27.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier B.V. All rights reserved. | ||
| 520 | |a Alzheimer's disease (AD) is one of the neurodegenerative disorder that primarily affects memory, thinking, and behavior, eventually leading to severe cognitive impairment. Therapeutic management of AD is urgently needed to improve the quality and lifestyle of patients. Tau phosphorylating kinases are considered attractive therapeutic targets. Microtubule affinity-regulating kinase 4 (MARK4) is directly linked with pathological phosphorylations of tau, highlighting its role in the therapeutic targeting of AD. The current manuscript shows the MARK4 inhibitory effect of Memantine (MEM), a drug used in treating AD. We have performed fluorescence based binding measurements, enzyme inhibition assay, docking and molecular dynamics (MD) simulations to understand the binding of of MARK4 and MEM and subsequent inhibition in the kinase activity. A 100 ns MD simulations provided a detailed analysis of MARK4-MEM complex and the role of potential critical residues in the binding. Finally, this study provides molecular insights into the therapeutic implication of MEM in AD therapeutics. We propose MEM effectively inhibits MARK4, it may be implicated in the development of targeted and efficient treatments for AD | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Alzheimer's disease | |
| 650 | 4 | |a Drug discovery | |
| 650 | 4 | |a Kinase inhibitors | |
| 650 | 4 | |a Molecular spectroscopy | |
| 650 | 4 | |a Structural dynamics | |
| 650 | 4 | |a Tauopathies | |
| 650 | 7 | |a Memantine |2 NLM | |
| 650 | 7 | |a W8O17SJF3T |2 NLM | |
| 650 | 7 | |a Protein Serine-Threonine Kinases |2 NLM | |
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| 700 | 1 | |a Choudhury, Arunabh |e verfasserin |4 aut | |
| 700 | 1 | |a Hussain, Afzal |e verfasserin |4 aut | |
| 700 | 1 | |a AlAjmi, Mohamed F |e verfasserin |4 aut | |
| 700 | 1 | |a Hassan, Md Imtaiyaz |e verfasserin |4 aut | |
| 700 | 1 | |a Islam, Asimul |e verfasserin |4 aut | |
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