Abstract
Coronavirus disease 2019 (COVID-19) has caused more than 840,000 deaths as of 31 August 2020 in the whole world. The COVID-19 main protease (M(pro)) has been validated as an attractive target for drug design. In this work, the binding mechanisms of five protease inhibitors (e.g., danoprevir, darunavir, ASC09, lopinavir and ritonavir) to COVID-19 M(pro) were investigated. Based on the docking score, five protease inhibitors structures were selected for further evaluation. It is found that most of the selected drug molecules bind stably to the COVID-19 M(pro) from the molecular dynamics simulation. Moreover, the MM/PBSA free energy calculations suggest that lopinavir with positive charge might be most active against COVID-19 M(pro).