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Article

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

1
Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, 44-100 Gliwice, Poland
2
Department of Physics, University of Alberta, Edmont, AB T6G 2E1, Canada
3
DIMEAS, Politecnino di Torino, Corso Duca degli Abruzzi, 24, 10129 Turin, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(9), 3099; https://doi.org/10.3390/ijms21093099
Received: 28 March 2020 / Revised: 20 April 2020 / Accepted: 26 April 2020 / Published: 28 April 2020
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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 drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mixed-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar severe acute respiratory syndrome (SARS) Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins showed major differences in both shape and size, indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site’s conformational changes during the simulation time indicated its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicated that the virus’ 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. View Full-Text
Keywords: coronavirus; SARS-CoV; SARS-CoV-2; COVID-19; molecular dynamics simulations; ligand tracking approach; drug design; small-molecule inhibitors; evolutionary analysis coronavirus; SARS-CoV; SARS-CoV-2; COVID-19; molecular dynamics simulations; ligand tracking approach; drug design; small-molecule inhibitors; evolutionary analysis
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MDPI and ACS Style

Bzówka, M.; Mitusińska, K.; Raczyńska, A.; Samol, A.; Tuszyński, J.A.; Góra, A. Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design. Int. J. Mol. Sci. 2020, 21, 3099. https://doi.org/10.3390/ijms21093099

AMA Style

Bzówka M, Mitusińska K, Raczyńska A, Samol A, Tuszyński JA, Góra A. Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design. International Journal of Molecular Sciences. 2020; 21(9):3099. https://doi.org/10.3390/ijms21093099

Chicago/Turabian Style

Bzówka, Maria, Karolina Mitusińska, Agata Raczyńska, Aleksandra Samol, Jack A. Tuszyński, and Artur Góra. 2020. "Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design" International Journal of Molecular Sciences 21, no. 9: 3099. https://doi.org/10.3390/ijms21093099

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