Sriranjini A S, Thapliyal Ashish, Pant Kumud
Department of Biotechnology, Graphic Era Deemed to be University, Dehradun, 248002 India.
In Silico Pharmacol. 2024 Mar 28;12(1):21. doi: 10.1007/s40203-024-00195-3. eCollection 2024.
The present research aims to explore the intricate link between SARS-CoV infection and susceptibility to Alzheimer's disease, focusing on the role of APOE4, a genetic factor associated with both conditions. Our research aims to uncover shared molecular pathways, considering APOE4's impact on lipid metabolism, immune responses, and neuroinflammation relevant to COVID-19 and AD. The Chyawanprash phytocompounds were subjected to in-silico ADMET profiling and Zeatin a neuroprotective cytokinin emerged as a promising regulator of the ACE2-SPIKE complex as it exhibits favourable pharmacological attributes, presenting as a non-substrate for Permeability glycoprotein, low Protein Binding Percentage, and distinctive toxicity endpoints. Therapeutic candidate. Zeatin's robust binding disrupts the intricate APOE4-ACE2-SPIKE interplay (AAS), offering a potential therapeutic avenue that is further corroborated by Molecular dynamic simulation as the system remained stable without any major fluctuation throughout the 100ns simulation. The AAS binding free energy, determined as -124.849 +/- 15.513 KJ/mol using MMPBSA assay, reveals significant contributions to complex stability from amino acids including, GLN41: 1.211 kcal/mol, GLU340: 1.188 kcal/mol, ALA344: 1.198 kcal/mol, while ARG38: 2.011 kcal/mol establishes pivotal strong bonds integral to the interaction between AAS and Zeatin. Rigorous cytotoxicity assessments reveal Zeatin's safety profile, highlighting its inhibitory effect on LN18 cell viability that sharply decreases to 32.47% at 200 µg/ml, underscoring its modulatory impact on cellular metabolism. These findings enhance our understanding of the convergent mechanisms linking SARS-CoV and AD, providing valuable insights for potential therapeutic interventions. Further research is warranted to elucidate the specific pathways and molecular mechanisms through which zeatin exerts its protective effects.
本研究旨在探讨严重急性呼吸综合征冠状病毒（SARS-CoV）感染与阿尔茨海默病易感性之间的复杂联系，重点关注载脂蛋白E4（APOE4）的作用，APOE4是与这两种疾病都相关的一个遗传因素。我们的研究旨在揭示共同的分子途径，考虑APOE4对与新冠病毒病（COVID-19）和阿尔茨海默病（AD）相关的脂质代谢、免疫反应和神经炎症的影响。对Chyawanprash植物化合物进行了计算机辅助的药物代谢及毒性预测分析，玉米素（一种具有神经保护作用的细胞分裂素）作为血管紧张素转换酶2（ACE2）-刺突蛋白复合物的一种有前景的调节剂脱颖而出，因为它具有良好的药理学特性，表现为不是通透性糖蛋白的底物、蛋白质结合率低以及有独特的毒性终点。治疗候选物。玉米素的强力结合破坏了复杂的APOE4-ACE2-刺突蛋白相互作用（AAS），提供了一条潜在的治疗途径，分子动力学模拟进一步证实了这一点，因为在整个100纳秒的模拟过程中系统保持稳定，没有任何重大波动。使用MMPBSA分析确定的AAS结合自由能为-124.849±15.513千焦/摩尔，揭示了包括谷氨酰胺41（GLN41）：1.211千卡/摩尔、谷氨酸340（GLU340）：1.188千卡/摩尔、丙氨酸344（ALA344）：1.198千卡/摩尔等氨基酸对复合物稳定性的显著贡献，而精氨酸38（ARG38）：2.011千卡/摩尔建立了对AAS与玉米素之间相互作用至关重要的强键。严格的细胞毒性评估揭示了玉米素的安全性，突出了其对LN18细胞活力具有抑制作用，在200微克/毫升时急剧降至32.47%，强调了其对细胞代谢的调节作用。这些发现增进了我们对将SARS-CoV与AD联系起来的趋同机制的理解，并为潜在的治疗干预提供了有价值信息。有必要进一步研究以阐明玉米素发挥其保护作用的具体途径和分子机制。
