Alzarea Sami I, Alsaidan Omar Awad, Alhassan Hassan H, Alzarea Abdulaziz Ibrahim, Alsahli Tariq G, Alharbi Metab, Afzal Muhammad, Sadiq Mantargi Mohammad Jaffar
Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Al-Jouf, Saudi Arabia.
King Salman Centre for Disability Research, Riyadh, Saudi Arabia.
Front Chem. 2025 May 30;13:1574702. doi: 10.3389/fchem.2025.1574702. eCollection 2025.
Neuraminidase in humans is studied to see how well repurposed oseltamivir works for treating Alzheimer's disease (AD) using methods like molecular docking, molecular dynamic (MD) simulation, and gene expression analysis. Gene enrichment analysis was also studied to understand the behaviour of neuraminidases in humans.
Molecular docking was done using oseltamivir and the neuraminidase proteins with the tool, and the results were analysed using BIOVIA Discovery Studio. MD simulation (50 ns) of the oseltamivir and neuraminidase complex was performed using GROMACS tools. The gene expression analysis and gene enrichment study were done using GEO2R, which showed the results as log FC and significant values. Enricher tool-based gene enrichment analysis was done to determine the gene behaviour related to the AD.
The molecular docking showed a strong connection between oseltamivir and neuraminidase (-6.5 kcal/mol), acetylcholinesterase (-7.9 kcal/mol), CDKs (-6.5 kcal/mol), and GSKs (-6.6 kcal/mol), interacting with different amino acids in the protein sequences. MD simulations showed a strong interaction between the ligand and neuraminidase, with stable measurements indicating that both the protein and ligand remained consistent in size and energy, which is better explained through the results of MM_PBSA and MM_GBSA analysis of the complex, resulting in the ΔE_vdW, ΔE_elec, ΔG_polar, ΔG_nonpolar, ΔG_gas, (ΔE_vdW + ΔEEL), ΔG_solvation: (ΔG_polar + ΔG_nonpolar) and ΔG_bind: total energies suggesting the complex stayed stable in conditions similar to those resembling natural cell. The gene expression analysis expressed TUBB3 (formation of beta-tubulin), FABP3 (regulates alpha-synuclein uptake in dopaminergic neurons), and CALM1 (calcium signal transduction pathway) to be highly upregulated in the given conditions with kinase binding (p = 0.0006541) and protein phosphatase regulatory activity (p = 0.001357) were highly upregulated, implicating their importance in the AD.
The study ends on a hopeful note for using oseltamivir to treat neurological diseases, but it suggests that future research should include a solid cell line study, an study, and a clinical study.
通过分子对接、分子动力学（MD）模拟和基因表达分析等方法，对人神经氨酸酶进行研究，以观察重新利用的奥司他韦治疗阿尔茨海默病（AD）的效果。还进行了基因富集分析，以了解人神经氨酸酶的行为。
使用奥司他韦和神经氨酸酶蛋白通过该工具进行分子对接，并使用BIOVIA Discovery Studio分析结果。使用GROMACS工具对奥司他韦和神经氨酸酶复合物进行MD模拟（50纳秒）。使用GEO2R进行基因表达分析和基因富集研究，结果以对数倍变化（log FC）和显著性值表示。基于Enricher工具进行基因富集分析，以确定与AD相关的基因行为。
分子对接显示奥司他韦与神经氨酸酶（-6.5千卡/摩尔）、乙酰胆碱酯酶（-7.9千卡/摩尔）、细胞周期蛋白依赖性激酶（CDKs，-6.5千卡/摩尔）和糖原合成酶激酶（GSKs，-6.6千卡/摩尔）之间有强烈的联系，它们与蛋白质序列中的不同氨基酸相互作用。MD模拟显示配体与神经氨酸酶之间有强烈的相互作用，稳定的测量结果表明蛋白质和配体在大小和能量上保持一致，通过复合物的MM_PBSA和MM_GBSA分析结果能更好地解释这一点，得出范德华能（ΔE_vdW）、静电能（ΔE_elec）、极性自由能（ΔG_polar）、非极性自由能（ΔG_nonpolar）、气相自由能（ΔG_gas）、（ΔE_vdW + ΔEEL）、溶剂化自由能（ΔG_solvation：（ΔG_polar + ΔG_nonpolar））和结合自由能（ΔG_bind）：总能量表明复合物在类似于天然细胞的条件下保持稳定。基因表达分析表明，在给定的激酶结合条件下，微管蛋白β3（TUBB3，β-微管蛋白的形成）、脂肪酸结合蛋白3（FABP3，调节多巴胺能神经元中α-突触核蛋白的摄取）和钙调蛋白1（CALM1，钙信号转导途径）高度上调（p = 0.0006541），蛋白磷酸酶调节活性（p = 0.001357）也高度上调，这表明它们在AD中的重要性。
该研究为使用奥司他韦治疗神经疾病带来了希望，但表明未来的研究应包括可靠的细胞系研究、一项[此处原文缺失相关内容]研究和一项临床研究。
