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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 Apr 28; 21(9)IJ

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 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.

Authors+Show Affiliations

Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, 44-100 Gliwice, Poland.Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, 44-100 Gliwice, Poland.Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, 44-100 Gliwice, Poland.Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, 44-100 Gliwice, Poland.Department of Physics, University of Alberta, Edmont, AB T6G 2E1, Canada. DIMEAS, Politecnino di Torino, Corso Duca degli Abruzzi, 24, 10129 Turin, Italy.Tunneling Group, Biotechnology Centre, ul. Krzywoustego 8, Silesian University of Technology, 44-100 Gliwice, Poland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32353978

Citation

Bzówka, Maria, et al. "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, vol. 21, no. 9, 2020.
Bzówka M, Mitusińska K, Raczyńska A, et al. 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(9).
Bzówka, M., Mitusińska, K., Raczyńska, A., Samol, A., Tuszyński, J. A., & Góra, A. (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(9). https://doi.org/10.3390/ijms21093099
Bzówka M, et al. 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 Apr 28;21(9) PubMed PMID: 32353978.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design. AU - Bzówka,Maria, AU - Mitusińska,Karolina, AU - Raczyńska,Agata, AU - Samol,Aleksandra, AU - Tuszyński,Jack A, AU - Góra,Artur, Y1 - 2020/04/28/ PY - 2020/03/28/received PY - 2020/04/20/revised PY - 2020/04/26/accepted PY - 2020/5/2/entrez PY - 2020/5/2/pubmed PY - 2020/5/6/medline KW - COVID-19 KW - SARS-CoV KW - SARS-CoV-2 KW - coronavirus KW - drug design KW - evolutionary analysis KW - ligand tracking approach KW - molecular dynamics simulations KW - small-molecule inhibitors JF - International journal of molecular sciences JO - Int J Mol Sci VL - 21 IS - 9 N2 - 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. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/32353978/Structural_and_Evolutionary_Analysis_Indicate_That_the_SARS_CoV_2_Mpro_Is_a_Challenging_Target_for_Small_Molecule_Inhibitor_Design_ L2 - https://www.mdpi.com/resolver?pii=ijms21093099 DB - PRIME DP - Unbound Medicine ER -