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《BioRxiv，3月2日，Molecular Dynamics Simulations Indicate the COVID-19 Mpro Is Not a Viable Target for Small-Molecule Inhibitors Design》

  • 来源专题：COVID-19科研动态监测
  • 编译者： zhangmin
  • 发布时间：2020-03-03

  • Molecular Dynamics Simulations Indicate the COVID-19 Mpro Is Not a Viable Target for Small-Molecule Inhibitors Design

    Maria Bzowka, Karolina Mitusinska, Agata Raczynska, Aleksandra Samol, Jack Adam Tuszynski, Artur Gora

    doi: https://doi.org/10.1101/2020.02.27.968008

    Abstract

    The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed molecular dynamics simulations of the main protease (Mpro). We compared and contrasted the Mpro for COVID-19 with a highly similar SARS protein.

    *注，本文为预印本论文手稿，是未经同行评审的初步报告，其观点仅供科研同行交流，并不是结论性内容，请使用者谨慎使用.

  • 原文来源：https://www.biorxiv.org/content/10.1101/2020.02.27.968008v1
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  • 《BioRxiv，3月19日，（第2版更新）Molecular Dynamics Simulations Indicate the SARS-CoV-2 Mpro Is Not a Viable Target for Small-Molecule Inhibitors Design》
    • 来源专题：COVID-19科研动态监测
    • 编译者：zhangmin
    • 发布时间：2020-03-20
    • Molecular Dynamics Simulations Indicate the SARS-CoV-2 Mpro Is Not a Viable Target for Small-Molecule Inhibitors Design Maria Bzowka, Karolina Mitusinska, Agata Raczynska, Aleksandra Samol, Jack Adam Tuszynski, Artur Gora doi: https://doi.org/10.1101/2020.02.27.968008 Abstract The coronavirus outbreak took place in December 2019 and continues to spread worldwide. In the absence of an effective vaccine, inhibitor repurposing may seem a fruitful attempt. Here, we compared Mpros from SARS-CoV-2 and SARS-CoV. Despite a high level of sequence similarity, the binding sites of analysed proteins show major differences in both shape and size indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, the analysis of the pockets' conformational changes during the simulation time indicates their flexibility, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the SARS-CoV-2 Mpro with respect to mutations of the binding cavity and adjacent flexible loops indicates that the protein's mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design. *注，本文为预印本论文手稿，是未经同行评审的初步报告，其观点仅供科研同行交流，并不是结论性内容，请使用者谨慎使用.
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  • 《3月19日_西里西亚工业大学研究表明SARS-CoV-2 Mpro不是设计其小分子抑制剂的可行目标》
    • 来源专题：COVID-19科研动态监测
    • 编译者：zhangmin
    • 发布时间：2020-03-20
    • 1.时间：2020年3月19日 2.机构或团队：西里西亚工业大学、阿尔伯塔大学 3.事件概要： 西里西亚工业大学于2020年3月19日在bioRxiv上发表题为“Molecular Dynamics Simulations Indicate the SARS-CoV-2 Mpro Is Not a Viable Target for Small-Molecule Inhibitors Design”的文章。文章中，研究人员比较了SARS-CoV-2和SARS-CoV的Mpro发现，尽管其序列相似性很高，但是蛋白质的结合位点在形状和大小上都显示出很大差异，这表明SARS药物可能无法用于COVID-19治疗。此外，在模拟过程中对囊袋构象变化的分析表明它们的灵活性，这打破了对快速设计可靠药物的希望。相反，SARS-CoV-2 Mpro相对于结合腔和相邻柔性环突变的结构稳定性表明，该蛋白的可变性将对小分子抑制剂的合理设计进一步提出挑战。 4.附件： 原文链接： https://www.biorxiv.org/content/10.1101/2020.02.27.968008v2
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