Atiya Akhtar, Alhumaydhi Fahad A, Shamsi Anas, Olatunde Ahmed, Alsagaby Suliman A, Al Abdulmonem Waleed, Sharaf Sharaf E, Shahwan Moyad
Department of Pharmacognosy, College of Pharmacy, King Khalid University (KKU), Guraiger St., Abha62529, Saudi Arabia.
Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah51452, Saudi Arabia.
ACS Omega. 2022 Oct 17;7(43):38361-38370. doi: 10.1021/acsomega.2c03185. eCollection 2022 Nov 1.
Huperzine A (HupA), an alkaloid found in the club moss , has been in use for centuries in Chinese traditional medicine to treat dementia owing to its ability to inhibit the cholinergic enzyme acetylcholinesterase (AChE), thus acting as an acetylcholinesterase inhibitor (AChEI). An imbalance of metal ions in the brain is linked to Alzheimer's disease (AD) pathology. Transferrin (Tf) is a crucial player in iron homeostasis, thus highlighting its significance in AD. This study explores the plausible binding of HupA with Tf using molecular docking, molecular dynamics (MD) simulation, and free energy landscape (FEL) analyses. The docking results show that HupA binds to the functionally active region of Tf by forming three hydrogen bonds with Thr392, Glu394, and Ser688 and several hydrophobic interactions. The MD simulation analyses show that HupA binding is stable with Tf, causing minimal changes to the protein conformation. Moreover, principal component analysis (PCA) and FEL also depict the stable binding of HupA with Tf without any significant fluctuations. Further, fluorescence-based binding suggested excellent binding affinity of HupA with Tf affirming observations. Isothermal titration calorimetry (ITC) advocated the spontaneous binding of HupA with Tf. This study provides an insight into the binding mechanism of HupA with Tf, and overall, the results show that HupA, after required experimentations, can be a better therapeutic agent for treating AD while targeting Tf.
石杉碱甲（HupA）是一种在石松中发现的生物碱，由于其能够抑制胆碱能酶乙酰胆碱酯酶（AChE），从而作为一种乙酰胆碱酯酶抑制剂（AChEI），在中国传统医学中已使用了数百年用于治疗痴呆症。大脑中金属离子的失衡与阿尔茨海默病（AD）的病理相关。转铁蛋白（Tf）是铁稳态的关键参与者，因此凸显了其在AD中的重要性。本研究使用分子对接、分子动力学（MD）模拟和自由能景观（FEL）分析来探索HupA与Tf之间可能的结合。对接结果表明，HupA通过与Thr392、Glu394和Ser688形成三个氢键以及若干疏水相互作用，与Tf的功能活性区域结合。MD模拟分析表明，HupA与Tf的结合是稳定的，对蛋白质构象的影响最小。此外，主成分分析（PCA）和FEL也描绘了HupA与Tf的稳定结合，没有任何明显波动。此外，基于荧光的结合表明HupA与Tf具有出色的结合亲和力，证实了观察结果。等温滴定量热法（ITC）支持HupA与Tf的自发结合。本研究深入了解了HupA与Tf的结合机制，总体而言，结果表明，经过所需的实验后，HupA在靶向Tf时可以成为治疗AD的更好治疗剂。
