背景:甲型流感病毒会导致严重的呼吸道疾病,特别是在发展中国家,大多数5岁以下的儿童死亡是由于下呼吸道感染造成的。RIG-I蛋白作为病毒dsRNA的传感器,通过TRIM25合成的K63连接的聚泛素链触发干扰素生产。然而,甲型流感病毒的NS1蛋白通过与TRIM25结合,破坏其与RIG-I的关联并阻止下游干扰素信号传导来阻碍这一过程,有助于病毒逃避免疫反应。
方法:在我们的研究中,我们使用基于结构的药物设计,分子模拟,和结合自由能方法从各种天然产物数据库(>100,000种化合物)中鉴定能够抑制NS1与TRIM25结合的有效植物化合物。
结果:分子筛选从东非天然产物数据库中鉴定出EA-8411902和EA-19951545,来自北非天然产物数据库的NA-390261和NA-71,SA-65230和SA-4477104来自南非天然化合物数据库,NEA-361和NEA-4524784来自东北非洲天然产品数据库,中药数据库中的TCM-4444713和TCM-6056排名第一。分子对接和结合自由能结果表明,这些化合物与参与与TRIM25相互作用的特定活性位点残基(Leu95,Ser99和Tyr89)具有高亲和力。此外,结构动力学分析,结合自由能,和解离常数表明这些化合物与NS1蛋白的结合亲和力明显更强。此外,所有选定的化合物都表现出优异的ADMET特性,包括高水溶性,胃肠吸收,没有肝毒性,同时坚持Lipinski的规则。
结论:我们的分子模拟结果强调,已鉴定的化合物对参与NS1-TRIM25相互作用的特定活性位点残基具有高亲和力,表现出优异的ADMET特性,并遵守类似药物的标准,从而为进一步开发抗甲型流感病毒感染的抗病毒药物提供了有希望的候选药物。
BACKGROUND: Influenza A virus causes severe respiratory illnesses, especially in developing nations where most child deaths under 5 occur due to lower respiratory tract infections. The RIG-I protein acts as a sensor for viral dsRNA, triggering interferon production through K63-linked poly-ubiquitin chains synthesized by TRIM25. However, the influenza A virus\'s NS1 protein hinders this process by binding to TRIM25, disrupting its association with RIG-I and preventing downstream interferon signalling, contributing to the virus\'s evasion of the immune response.
METHODS: In our study we used structural-based drug designing, molecular simulation, and binding free energy approaches to identify the potent phytocompounds from various natural product databases (>100,000 compounds) able to inhibit the binding of NS1 with the TRIM25.
RESULTS: The molecular screening identified EA-8411902 and EA-19951545 from East African Natural Products Database, NA-390261 and NA-71 from North African Natural Products Database, SA-65230 and SA- 4477104 from South African Natural Compounds Database, NEA- 361 and NEA- 4524784 from North-East African Natural Products Database, TCM-4444713 and TCM-6056 from Traditional Chinese Medicines Database as top hits. The molecular docking and binding free energies results revealed that these compounds have high affinity with the specific active site residues (Leu95, Ser99, and Tyr89) involved in the interaction with TRIM25. Additionally, analysis of structural dynamics, binding free energy, and dissociation constants demonstrates a notably stronger binding affinity of these compounds with the NS1 protein. Moreover, all selected compounds exhibit exceptional ADMET properties, including high water solubility, gastrointestinal absorption, and an absence of hepatotoxicity, while adhering to Lipinski\'s rule.
CONCLUSIONS: Our molecular simulation findings highlight that the identified compounds demonstrate high affinity for specific active site residues involved in the NS1-TRIM25 interaction, exhibit exceptional ADMET properties, and adhere to drug-likeness criteria, thus presenting promising candidates for further development as antiviral agents against influenza A virus infections.