Shamsi Anas, Shahwan Moyad, Khan Mohd Shahnawaz, Husain Fohad Mabood, Alhumaydhi Fahad A, Aljohani Abdullah S M, Rehman Md Tabish, Hassan Md Imtaiyaz, Islam Asimul
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, UAE.
ACS Omega. 2021 Mar 11;6(11):7922-7930. doi: 10.1021/acsomega.1c00527. eCollection 2021 Mar 23.
Recent research has advocated the significant contribution of metal dyshomeostasis in developing and progressing Alzheimer's disease (AD). Disruption of homeostasis creates an imbalance of the metal ions that causes neuronal dysfunction and death. Flavonoids such as quercetin and naringenin play an essential role in iron homeostasis and are widely explored in treating various complex diseases. Iron is a critical player in many physiological activities, and hence, its homeostasis is essential for the normal functioning of the brain. Iron deficiency and iron overload contribute to AD development, highlighting the importance of maintaining iron homeostasis. Ferritin is an iron protein associated with the storage and sequestration of excess ferrous iron, playing a pivotal role in maintaining iron levels. Flavonoids are the most common polyphenolic compounds present in the human diet and are known to exert multiple neuroprotective actions. Naringenin and quercetin are extensively explored polyphenols having a broad range of therapeutic potential ranging from cancers to neurodegenerative disorders. This study aims to investigate their binding, employing molecular docking and molecular dynamics (MD) simulation in light of these polyphenols' and ferritin's therapeutic importance in AD. In this study, we performed structure-based docking of quercetin and naringenin with human ferritin. First, the binding affinity of quercetin and naringenin toward ferritin was estimated, and then their close interactions were explored to find the stable poses. All-atom 100 ns MD simulations further escorted the docking study, followed by principal component and free energy landscape analyses. The dynamic studies helped investigate the conformational dynamic, structural stability, and interaction mechanism of ferritin with quercetin and naringenin. The MD analysis suggested that the binding of quercetin and naringenin with ferritin stabilizes throughout the simulation period and leads to fewer conformational deviations. This study gives an insight at the atomistic level into the interaction between quercetin and naringenin with ferritin, thereby aiding in understanding the activity and mechanism of protein and drug binding. The study is clinically significant as iron participates in the occurrence of AD.
最近的研究表明，金属稳态失衡在阿尔茨海默病（AD）的发生和发展过程中起着重要作用。体内稳态的破坏会导致金属离子失衡，进而引起神经元功能障碍和死亡。槲皮素和柚皮素等类黄酮在铁稳态中发挥着重要作用，并且在治疗各种复杂疾病方面得到了广泛研究。铁在许多生理活动中起着关键作用，因此，其稳态对于大脑的正常功能至关重要。铁缺乏和铁过载都有助于AD的发展，这凸显了维持铁稳态的重要性。铁蛋白是一种与过量亚铁储存和螯合相关的铁蛋白，在维持铁水平方面起着关键作用。类黄酮是人类饮食中最常见的多酚化合物，已知具有多种神经保护作用。柚皮素和槲皮素是经过广泛研究的多酚，具有从癌症到神经退行性疾病等广泛的治疗潜力。鉴于这些多酚和铁蛋白在AD中的治疗重要性，本研究旨在通过分子对接和分子动力学（MD）模拟来研究它们之间的结合。在本研究中，我们对槲皮素和柚皮素与人铁蛋白进行了基于结构的对接。首先，估计了槲皮素和柚皮素对铁蛋白的结合亲和力，然后探索它们的紧密相互作用以找到稳定构象。全原子100 ns MD模拟进一步辅助了对接研究，随后进行了主成分分析和自由能景观分析。动力学研究有助于研究铁蛋白与槲皮素和柚皮素的构象动力学、结构稳定性及相互作用机制。MD分析表明，槲皮素和柚皮素与铁蛋白的结合在整个模拟过程中保持稳定，并且导致较少的构象偏差。本研究在原子水平上深入了解了槲皮素和柚皮素与铁蛋白之间的相互作用，从而有助于理解蛋白质与药物结合的活性和机制。由于铁参与AD的发生，该研究具有临床意义。
