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Structural and Evolutionary Analysis Indicate that the SARS-CoV-2 Mpro is an Inconvenient Target for Small-Molecule Inhibitors Design

By Maria Bzówka, Karolina Mitusińska, Agata Raczyńska, Aleksandra Samol, J. A.Tuszynski, Artur Góra

Posted 02 Mar 2020
bioRxiv DOI: 10.1101/2020.02.27.968008 (published DOI: 10.3390/ijms21093099)

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 mix-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 SARS Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins show 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 indicates 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 indicates 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. * Mpro : Main protease CoVs : Coronaviruses ORFs : Open reading frames 3CLpro : Chymotrypsin-like cysteine protease S : Spike surface glycoprotein E : Small envelope protein M : Matrix protein N : Nucleocapsid protein N3 : N-[(5 methylisoxazol-3-yl)carbonyl] alanyl-L-valyl-N~1-((1R,2Z)-4-(benzyloxy)-4-oxo-1--{[(3R)-2-oxopyrrolidin-3-yl]methyl}but-2-enyl)-L-leucinamide cMD : Classical molecular dynamics simulations MixMD : Mixed-solvent molecular dynamics simulations PDB : Protein Data Bank MAV : Maximal accessible volume ACN : Acetonitrile BNZ : Benzene DMSO : Dimethylsulfoxide MEO : Methanol PHN : Phenol URE : Urea CMA : Correlated mutation analysis

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