Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Int J Biol Macromol. 2024 Mar;262(Pt 2):130090. doi: 10.1016/j.ijbiomac.2024.130090. Epub 2024 Feb 9.
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.
阿尔茨海默病（AD）是一种神经退行性疾病，主要影响记忆、思维和行为，最终导致严重的认知障碍。迫切需要对 AD 进行治疗管理，以提高患者的生活质量。tau 磷酸化激酶被认为是有吸引力的治疗靶点。微管亲和调节激酶 4（MARK4）与 tau 的病理性磷酸化直接相关，突出了其在 AD 治疗靶向中的作用。本文显示了 Memantine（MEM）对 MARK4 的抑制作用，MEM 是一种用于治疗 AD 的药物。我们进行了荧光结合测量、酶抑制测定、对接和分子动力学（MD）模拟，以了解 MARK4 和 MEM 的结合以及随后对激酶活性的抑制。100ns MD 模拟提供了 MARK4-MEM 复合物的详细分析，以及结合中潜在关键残基的作用。最后，这项研究为 MEM 在 AD 治疗中的治疗意义提供了分子见解。我们提出 MEM 能有效抑制 MARK4，它可能与 AD 的靶向和有效治疗的发展有关。
