预测建模和基于片段设计的三类核酸合物针对冠状病毒膜融合
Mengyang Wang1, Xingxing Zhu2, Shouxin Wang3
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
European journal of medicinal chemistry
|December 24, 2025
概括
三聚胺-核酸合物显示出作为SARS-CoV-2进入抑制剂的前景. 机器学习引导了发现那些通过准Spike蛋白质来阻止病毒进入的化合物的发现.
科学领域:
- 药用化学 医学化学
- 病毒学 病毒学
- 计算生物学 计算生物学
背景情况:
- 三类植物具有多样化的生物活动.
- 三类药物对SARS-CoV-2的抗病毒潜力需要进一步调查.
- 准Spike蛋白的融合-heptad重复1 (FP-HR1) 接口是抑制病毒进入的一个策略.
研究的目的:
- 开发一种用于识别新型SARS-CoV-2进入抑制剂的计算模型.
- 设计和合成具有抗病毒活性的新型三烯酸核酸衍生物.
- 为了评估这些衍生品对SARS-CoV-2伪病毒的疗效.
主要方法:
- 使用抗病毒数据集开发一个堆叠集团机器学习模型.
- 在复合设计中应用基于碎片的组装策略.
- 使用伪病毒进入试验和生物物理分析对化合物疗效的实验性评估.
主要成果:
- 开发了一个具有74.17%准确度和0.85 AUC的机器学习模型.
- 九种新型的三基核酸衍生物在15μM时表现出超过80%的抑制.
- 鉴定的化合物显示了微分子EC50值对野生类型和Omicron SARS-CoV-2伪病毒.
- 发现化合物干扰了Spike S2子单元的FP-HR1接口的病毒进入.
结论:
- 三聚酸核酸合物是有效的SARS-CoV-2进入抑制剂.
- 开发的计算方法加速了抗病毒化合物的发现.
- 这些发现突出了一个有前途的新类抗病毒药物,针对病毒进入机制.
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