Alrouji Mohammed, Yasmin Sabina, Alhumaydhi Fahad A, Sharaf Sharaf E, Shahwan Moyad, Furkan Mohammad, Khan Rizwan Hasan, Shamsi Anas
Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra, Saudi Arabia.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia.
Front Pharmacol. 2024 May 10;15:1397332. doi: 10.3389/fphar.2024.1397332. eCollection 2024.
In present times, vanillin stands out as a promising therapeutic molecule that can be implicated in the treatment of neurodegenerative disorders (NDs), notably Alzheimer's disease (AD). This can be attributed to the highly potent scavenging activity of vanillin against reactive oxygen species (ROS). Oxidative stress leads to generation of ROS that serves a critical role in AD's pathological progression. It is apparent from various studies that diets rich in polyphenols prevent oxidative stress associated with AD development, implying the crucial role of vanillin in AD therapeutics. It is crucial to maintain iron balance to manage AD associated oxidative stress, unveiling the significance of human transferrin (hTf) that maintains iron homeostasis. Here, we have performed an integrated study of spectroscopic and computational approaches to get insight into the binding mechanism of vanillin with hTf. In the preliminary study, molecular docking deciphered that vanillin primarily occupies the hTf binding pocket, forming multiple interactions with its key residues. Moreover, the binding mechanism was evaluated at an atomistic level employing comprehensive molecular dynamic (MD) simulation. MD analysis demonstrated that binding of vanillin to hTf stabilizes its structure, without inducing any significant alterations in its native conformation. The docked complex was maintained throughout the simulations without changing its original conformation. Essential dynamics analysis further confirms that hTf achieved a stable conformation with vanillin. The outcomes were further supplemented by fluorescence spectroscopy which confirms the formation of stable hTf-vanillin complex. Taken together, the current study unveils the interaction mechanism of vanillin with hTf and providing a platform to use vanillin in AD therapeutics in the context of iron homeostasis.
在当今时代，香草醛是一种很有前景的治疗分子，可用于治疗神经退行性疾病（NDs），尤其是阿尔茨海默病（AD）。这归因于香草醛对活性氧（ROS）具有高效的清除活性。氧化应激导致ROS的产生，而ROS在AD的病理进展中起关键作用。从各种研究中可以明显看出，富含多酚的饮食可预防与AD发展相关的氧化应激，这意味着香草醛在AD治疗中起着至关重要的作用。维持铁平衡对于控制与AD相关的氧化应激至关重要，这揭示了维持铁稳态的人转铁蛋白（hTf）的重要性。在这里，我们进行了光谱和计算方法的综合研究，以深入了解香草醛与hTf的结合机制。在初步研究中，分子对接表明香草醛主要占据hTf的结合口袋，与其关键残基形成多种相互作用。此外，在原子水平上采用全面的分子动力学（MD）模拟评估了结合机制。MD分析表明，香草醛与hTf的结合使其结构稳定，而不会在其天然构象中引起任何显著变化。对接复合物在整个模拟过程中保持不变，没有改变其原始构象。主成分动力学分析进一步证实hTf与香草醛形成了稳定的构象。荧光光谱进一步补充了研究结果，证实了稳定的hTf - 香草醛复合物的形成。综上所述，当前的研究揭示了香草醛与hTf的相互作用机制，并提供了一个在铁稳态背景下将香草醛用于AD治疗的平台。
