突变诱导的SARS-CoV-2对WU-04的Mpro耐药性通过多规模建模揭示
Mengting Liu1,2,3,4, Derui Zhao2,3, Hui Duan2,3
1College of Pharmacy, Dali University, Dali 671003, China.
International journal of molecular sciences
|January 28, 2026
概括
了解SARS-CoV-2主要蛋白酶 (Mpro) 突变是耐用抗病毒药物的关键. 这项研究揭示了特定突变如何影响抑制剂WU-04结合,并确定了设计更有弹性的Mpro抑制剂的途径.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
背景情况:
- 由于新出现的耐药性突变,SARS-CoV-2主要蛋白酶 (Mpro) 抑制剂的临床耐用性受到挑战.
- 在Mpro位置49,165和301的替代引起了人们对WU-04等非对应抑制剂对SARS-CoV-2变体的疗效的担忧.
研究的目的:
- 研究SARS-CoV-2 Mpro耐药性突变对非共价抑制剂WU-04的结合亲和力和动态的影响.
- 确定结构和动态途径,可以为下一代Mpro抑制剂的设计提供信息,具有增强的突变耐受性.
主要方法:
- 利用了微秒级分子动力学模拟和结合的自由能量计算.
- 采用网络重新布线推断 (NRI) 框架来绘制Mpro维度内的远程动态通信.
- 评估的野生类型 (WT) 是Mpro,单基因突变 (M49K,M165V,S301P) 和双基因突变 (M49K和M165V,M49K和S301P).
主要成果:
- 单个Mpro突变将WU-04的结合亲和力降低了高达~12kcal/mol,改变了S2子位点和配体相互作用.
- 双重突变M49K/S301P的WU-04结合部分恢复,亲和力得到改善,重建了关键联系.
- NRI分析显示,残留301突变可以重新连接域间通信,可能弥补残留49的局部干扰.
结论:
- 特定的Mpro突变显著损害了抑制剂结合,但双重突变可以部分恢复疗效.
- 远程动态通信通路,特别是涉及301残留物,在Mpro抑制剂弹性中起着至关重要的作用.
- 未来的Mpro抑制剂设计应专注于独立于S2口袋的相互作用,并参与像165-166骨干这样的保护区域来克服阻力.
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