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

• DOI: 10.3390/ijms21093099
• Publication Date: 2020-04-28T14:30:58Z
• Authors: Maria Bzówka; Karolina Mitusińska; Agata Raczyńska; Aleksandra Samol; Jack A. Tuszyński; Artur Góra
• Keywords: 2019-20 coronavirus outbreak

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 longer-term strategy combat this and future infections due similar viruses. Here, we report on detailed classical mixed-solvent molecular dynamics simulations main protease (Mpro) enriched by evolutionary stability analysis protein. results were compared with those for highly severe acute respiratory syndrome (SARS) Mpro spite high level sequence similarity, active sites both proteins showed major differences shape size, indicating that SARS drugs COVID-19 be futile. Furthermore, binding site's conformational changes during simulation time indicated its flexibility plasticity, which dashes hopes reliable design. Conversely, structural protein respect flexible loop mutations virus' mutability will pose further challenge rational small-molecule inhibitors. However, few residues contribute significantly thus can considered as key anchoring