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对SARS-CoV-2 Mpro酶的342个晶体全结构的计算评估和基准研究

Hamlet Khachatryan^1,2, Mher Matevosyan³, Vardan Harutyunyan³

¹Denovo Sciences Inc, 0060, Yerevan, Armenia. hamletk@denovosciences.ai.

Scientific reports

|June 20, 2024

概括

选择正确的严重急性呼吸系统综合征冠状病毒2 (SARS-CoV-2) 主蛋白酶 (Mpro) 结构是有效的基于结构的虚拟查 (SBVS) 的关键. 选择不当的形状导致药物发现结果不准确.

科学领域:

药物发现药物发现药物发现
结构生物学结构生物学
计算化学的计算化学

背景情况:

由SARS-CoV-2引起的COVID-19大流行,需要新的抗病毒疗法.
由于其在病毒复制中的作用,SARS-CoV-2主蛋白酶 (Mpro) 是药物开发的关键目标.
现有的治疗方法不足,导致需要先进的药物发现方法.

研究的目的:

系统地评估SARS-CoV-2 Mpro全晶结构,以在基于结构的虚拟查 (SBVS) 中进行最佳选择.
为了识别阻碍或促进准确的虚拟查结果的特定Mpro形状.
为改善药物发现提供对影响对接性能的结构特征的见解.

主要方法:

对342个SARS-CoV-2 Mpro全晶结构的系统分析.
使用了三个对接程序 (AutoDock Vina,rDock,Glide) 来进行虚拟选效率评估.
评估基于结构的虚拟查性能,使用EF,AUC和BEDROCK等指标,以及姿势预测准确性.

主要成果:

在评估的Mpro结构中观察到有限的结构灵活性.
结构5RHE,7DDC和7DPU始终产生最差的性能指标 (低EF,AUC,BEDROCK) 并提出预测.
关键的结构变化,包括S1子站点的缺失和S2子口袋的存在,与非最佳对接结果相关.

结论:

选择适当的SARS-CoV-2 Mpro形状对于基于结构的虚拟查的成功至关重要.
某些Mpro PDB条目 (5RHE,7DDC,7DPU) 的特定结构特征会对虚拟选准确性产生负面影响.
这些发现为优化SBVS策略在SARS-CoV-2治疗药物的开发中提供了宝贵的指导.

关键词:

在 COVID-19 疫情中,合规性分析是指对合规性的分析.新冠病毒新冠病毒新冠病毒.在Mpro Mpro中使用.结构性集群是指结构性的集群.虚拟选是一个虚拟的选.

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