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针对 SARS-CoV-2 主蛋白酶 (Mpro) 的突变抑制剂的结构导向设计和三重分子动力学评估

Ankita Bhagat¹, Lakshmi Mounika Kelam¹, Nilanjan Samanta¹

¹Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S Nagar, Mohali, Punjab 160062 India.

In silico pharmacology

|September 8, 2025

概括

研究人员设计了突变来抑制SARS-CoV-2主要蛋白酶 (Mpro). M3 (FLFPFR) 显示出最高的稳定性和最低的结合能,表明其作为有效的抗病毒疗法的潜力.

科学领域:

生物化学和分子生物学
药物发现和开发药物发现和开发
计算化学计算化学

背景情况:

在SARS-CoV-2的流行突出了有效的抗病毒治疗的必要性.
SARS-CoV-2 主蛋白酶 (Mpro) 对于病毒复制至关重要,也是关键的药物标.

研究的目的:

设计和评估针对SARS-CoV-2的新型抑制剂 Mpro.
确定具有增强结合亲和力和结构稳定性的Mpro抑制剂.

主要方法:

系统性突变被引入一个已知的Mpro切割部位 (QLMPER).
通过对接,分子动力学 (MD) 模拟和MM-GBSA计算,对214个突变的库进行了选.
通过广泛的MD模拟和计算光谱分析,进一步评估了顶级候选者的稳定性和结合自由能量.

主要成果:

25个单基因突变和70个多基因突变与Mpro.有显著的相互作用.
与野生类型 (-4.28 kcal/mol) 相比,M3突变 (FLFPFR) 显示出优越的结构稳定性和最低的结合自由能量 (-34 kcal/mol).
计算分析证实突变诱导了结构变化并增强了M3的反应能力.

结论:

理性设计的M3 (FLFPFR) 是SARS-CoV-2抑制的非常有前途的候选者.
这项研究验证了通过计算设计开发的基于的抑制剂的潜力,用于抗病毒药物发现.

关键词:

模拟MD的模拟方法在MM-GBSA中使用.突变突变是一种突变.十一月十一日 Nsp 10/11 这是一种类.在SARS-CoV-2主要蛋白酶 (Mpro) 中.

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