Molecular Dynamics Simulations Indicate the SARS-CoV-2 Mpro Is Not a Viable Target for Small-Molecule Inhibitors Design

Maria Bzówka; Karolina Mitusinska; Agata Raczynska; Aleksandra Samol; Jack Tuszynski; Artur Góra

In early December 2019, the first atypical pneumonia outbreak associated with the novel coronavirus of zoonotic origin (SARS-CoV-2) appeared in Wuhan City, Hubei Province, China [1, 2] . In general, coronaviruses (CoVs) are classified into four major genera: Alphacoronavirus, Betacoronavirus (which primarily infect mammals), Gammacoronavirus, and Deltacoronavirus (which primarily infect birds) [3] [4] [5] . In humans, coronaviruses usually cause mild to moderate upper-respiratory tract illnesses, e.g., the common cold, however, the rarer forms of CoVs can be lethal. By the end of 2019, six kinds of human CoV have been identified: HCoV-NL63, HCoV-229E, belonging to Alphacoronavirus genera, HCoV-OC43, HCoV-HKU1, severe acute respiratory syndrome SARS-CoV, and Middle East respiratory syndrome MERS-CoV, belonging to Betacoronavirus genera [4] . Of the aforementioned CoVs, the last two are the most dangerous and they were associated with the outbreak of two epidemics at the beginning of the 21st century [6] . On January 2020, SARS-CoV-2 was isolated and announced as a new, seventh, type of human coronavirus. It was classified as Betacoronavirus [2] . Based on the phylogenetic analysis of the genomic data of SARS-CoV-2, Zhang et al. indicated that the SARS-CoV-2 is most closely related to two SARS-CoV sequences isolated from bats in 2015 and 2017. This is suggestive that the bat's CoV and SARS-CoV-2 share a common ancestor, and the new virus can be considered as a SARS-like virus [7] .