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 “neurofibrillary tangles,” a histopathological hallmark associated with onset AD and related tauopathies. Microtubule-affinity regulating kinase 4 (MARK4) evolutionarily conserved Ser-Thr (S/T) that phosphorylates microtubule-associated proteins, thus playing critical role pathology. The uncontrolled neuronal migration attributed overexpressed MARK4, disruption microtubule dynamics. Inhibiting MARK4 attractive strategy therapeutics. Methods: Molecular docking was performed see interactions between galantamine (GLT). Furthermore, 250 ns molecular dynamic studies were investigate stability conformational dynamics MARK4–GLT complex. We fluorescence binding isothermal titration calorimetry measure affinity GLT MARK4. Finally, enzyme inhibition assay activity presence absence GLT. Results: showed GLT, acetylcholinesterase inhibitor, binds active site cavity appreciable affinity. simulation for demonstrated Fluorescence suggested strong further show inhibits significantly (IC 50 = 5.87 µM). Conclusion: These results suggest potential inhibitor could be promising therapeutic target AD. GLT’s provides newer insights into mechanism action, which already used improve cognition patients.