Cargando…
Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease
Introduction: Hyperphosphorylation of tau is an important event in Alzheimer’s disease (AD) pathogenesis, leading to the generation of “neurofibrillary tangles,” a histopathological hallmark associated with the onset of AD and related tauopathies. Microtubule-affinity regulating kinase 4 (MARK4) is...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10546050/ https://www.ncbi.nlm.nih.gov/pubmed/37795023 http://dx.doi.org/10.3389/fphar.2023.1276179 |
_version_ | 1785114792702246912 |
---|---|
author | Adnan, Mohd DasGupta, Debarati Anwar, Saleha Shamsi, Anas Siddiqui, Arif Jamal Snoussi, Mejdi Bardakci, Fevzi Patel, Mitesh Hassan, Md Imtaiyaz |
author_facet | Adnan, Mohd DasGupta, Debarati Anwar, Saleha Shamsi, Anas Siddiqui, Arif Jamal Snoussi, Mejdi Bardakci, Fevzi Patel, Mitesh Hassan, Md Imtaiyaz |
author_sort | Adnan, Mohd |
collection | PubMed |
description | Introduction: Hyperphosphorylation of tau is an important event in Alzheimer’s disease (AD) pathogenesis, leading to the generation of “neurofibrillary tangles,” a histopathological hallmark associated with the onset of AD and related tauopathies. Microtubule-affinity regulating kinase 4 (MARK4) is an evolutionarily conserved Ser-Thr (S/T) kinase that phosphorylates tau and microtubule-associated proteins, thus playing a critical role in AD pathology. The uncontrolled neuronal migration is attributed to overexpressed MARK4, leading to disruption in microtubule dynamics. Inhibiting MARK4 is an attractive strategy in AD therapeutics. Methods: Molecular docking was performed to see the interactions between MARK4 and galantamine (GLT). Furthermore, 250 ns molecular dynamic studies were performed to investigate the stability and conformational dynamics of the MARK4–GLT complex. We performed fluorescence binding and isothermal titration calorimetry studies to measure the binding affinity between GLT and MARK4. Finally, an enzyme inhibition assay was performed to measure the MARK4 activity in the presence and absence of GLT. Results: We showed that GLT, an acetylcholinesterase inhibitor, binds to the active site cavity of MARK4 with an appreciable binding affinity. Molecular dynamic simulation for 250 ns demonstrated the stability and conformational dynamics of the MARK4–GLT complex. Fluorescence binding and isothermal titration calorimetry studies suggested a strong binding affinity. We further show that GLT inhibits the kinase activity of MARK4 significantly (IC(50) = 5.87 µM). Conclusion: These results suggest that GLT is a potential inhibitor of MARK4 and could be a promising therapeutic target for AD. GLT’s inhibition of MARK4 provides newer insights into the mechanism of GLT’s action, which is already used to improve cognition in AD patients. |
format | Online Article Text |
id | pubmed-10546050 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-105460502023-10-04 Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease Adnan, Mohd DasGupta, Debarati Anwar, Saleha Shamsi, Anas Siddiqui, Arif Jamal Snoussi, Mejdi Bardakci, Fevzi Patel, Mitesh Hassan, Md Imtaiyaz Front Pharmacol Pharmacology Introduction: Hyperphosphorylation of tau is an important event in Alzheimer’s disease (AD) pathogenesis, leading to the generation of “neurofibrillary tangles,” a histopathological hallmark associated with the onset of AD and related tauopathies. Microtubule-affinity regulating kinase 4 (MARK4) is an evolutionarily conserved Ser-Thr (S/T) kinase that phosphorylates tau and microtubule-associated proteins, thus playing a critical role in AD pathology. The uncontrolled neuronal migration is attributed to overexpressed MARK4, leading to disruption in microtubule dynamics. Inhibiting MARK4 is an attractive strategy in AD therapeutics. Methods: Molecular docking was performed to see the interactions between MARK4 and galantamine (GLT). Furthermore, 250 ns molecular dynamic studies were performed to investigate the stability and conformational dynamics of the MARK4–GLT complex. We performed fluorescence binding and isothermal titration calorimetry studies to measure the binding affinity between GLT and MARK4. Finally, an enzyme inhibition assay was performed to measure the MARK4 activity in the presence and absence of GLT. Results: We showed that GLT, an acetylcholinesterase inhibitor, binds to the active site cavity of MARK4 with an appreciable binding affinity. Molecular dynamic simulation for 250 ns demonstrated the stability and conformational dynamics of the MARK4–GLT complex. Fluorescence binding and isothermal titration calorimetry studies suggested a strong binding affinity. We further show that GLT inhibits the kinase activity of MARK4 significantly (IC(50) = 5.87 µM). Conclusion: These results suggest that GLT is a potential inhibitor of MARK4 and could be a promising therapeutic target for AD. GLT’s inhibition of MARK4 provides newer insights into the mechanism of GLT’s action, which is already used to improve cognition in AD patients. Frontiers Media S.A. 2023-09-19 /pmc/articles/PMC10546050/ /pubmed/37795023 http://dx.doi.org/10.3389/fphar.2023.1276179 Text en Copyright © 2023 Adnan, DasGupta, Anwar, Shamsi, Siddiqui, Snoussi, Bardakci, Patel and Hassan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Adnan, Mohd DasGupta, Debarati Anwar, Saleha Shamsi, Anas Siddiqui, Arif Jamal Snoussi, Mejdi Bardakci, Fevzi Patel, Mitesh Hassan, Md Imtaiyaz Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease |
title | Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease |
title_full | Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease |
title_fullStr | Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease |
title_full_unstemmed | Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease |
title_short | Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease |
title_sort | mechanistic insights into mark4 inhibition by galantamine toward therapeutic targeting of alzheimer’s disease |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10546050/ https://www.ncbi.nlm.nih.gov/pubmed/37795023 http://dx.doi.org/10.3389/fphar.2023.1276179 |
work_keys_str_mv | AT adnanmohd mechanisticinsightsintomark4inhibitionbygalantaminetowardtherapeutictargetingofalzheimersdisease AT dasguptadebarati mechanisticinsightsintomark4inhibitionbygalantaminetowardtherapeutictargetingofalzheimersdisease AT anwarsaleha mechanisticinsightsintomark4inhibitionbygalantaminetowardtherapeutictargetingofalzheimersdisease AT shamsianas mechanisticinsightsintomark4inhibitionbygalantaminetowardtherapeutictargetingofalzheimersdisease AT siddiquiarifjamal mechanisticinsightsintomark4inhibitionbygalantaminetowardtherapeutictargetingofalzheimersdisease AT snoussimejdi mechanisticinsightsintomark4inhibitionbygalantaminetowardtherapeutictargetingofalzheimersdisease AT bardakcifevzi mechanisticinsightsintomark4inhibitionbygalantaminetowardtherapeutictargetingofalzheimersdisease AT patelmitesh mechanisticinsightsintomark4inhibitionbygalantaminetowardtherapeutictargetingofalzheimersdisease AT hassanmdimtaiyaz mechanisticinsightsintomark4inhibitionbygalantaminetowardtherapeutictargetingofalzheimersdisease |