人工智能促进了虚拟选,基于结构的打击优化和新型COVID-19 S-RBD域抑制剂的合成
Ioannis Gkekas1, Sotirios Katsamakas2,3, Stelios Mylonas2
1Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece.
Journal of chemical information and modeling
|November 13, 2024
概括
研究人员发现了一种新型的胺衍生物,CPP-25,它有效地抑制了SARS-CoV-2进入细胞. 这种化合物通过阻断尖端蛋白-ACE2相互作用,显示出作为潜在的治疗剂对抗COVID-19的承诺.
科学领域:
- 病毒学 病毒学
- 药物发现 药物发现 药物发现
- 计算化学计算化学
背景情况:
- 严重急性呼吸系统综合征-冠状病毒-2 (SARS-CoV-2) 利用其尖端 (S) 糖蛋白与宿主细胞上的血管素转化酶II (ACE2) 受体结合,促进病毒的进入.
- 准S蛋白-ACE2相互作用是针对2019年新冠肺炎疾病 (COVID-19) 开发抗病毒疗法的可行策略.
研究的目的:
- 确定能够抑制SARS-CoV-2 S蛋白质受体结合域 (RBD) 与人类ACE2受体之间的相互作用的小分子.
- 发现和优化具有针对SARS-CoV-2潜在抗病毒活性的化合物.
主要方法:
- 使用基于AI的管道对大型化合物库进行虚拟选,以识别与SARS-CoV-2 RBD结合的分子.
- 试验室试验评估已识别的化合物对Spike RBD/ACE2相互作用和病毒感染的抑制作用.
- 通过合成衍生品和随后的体外ADME-Tox分析来优化击中到.
主要成果:
- 最初的查产生了31种命中化合物,其中6种表明S-ACE2相互作用的剂量依赖抑制.
- 两种化合物防止了伪型病毒感染,一种是胺醇衍生物CPK-22,保护了Vero E6细胞免受SARS-CoV-2感染.
- 优化的衍生品CKP-25显著抑制了S-ACE2相互作用 (IC50 = 3.5μM),降低了病毒载量,并在体外表现出有利的ADME-Tox特性,包括微弱的CYP450抑制和无突变性.
结论:
- CKP-25是SARS-CoV-2 S-ACE2相互作用的强有力的抑制剂,并且在体外表现出显著的抗病毒活性.
- CKP-25具有有利的药理动力学和安全性概况,将其定位为一个有希望的化合物,用于进一步开发COVID-19治疗药物.
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