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 design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed molecular dynamics simulations of the main protease (Mpro). We compared and contrasted the Mpro for COVID-19 with a highly similar SARS 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 pocket’s time-dependence 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.
