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.
