Exploring the inhibition mechanism of SARS‐CoV‐2 main protease by ebselen: A molecular docking, molecular dynamics simulation and DFT approach

Abstract The main protease (Mpro) of SARS‐CoV‐2 plays an essential role in the virus life cycle and is considered a key target for therapeutic development. This study explores the inhibition mechanism of SARS‐CoV‐2 Mpro by ebselen, an organoselenium drug that shows potent inhibitory activity. By using a combination of multiple computational methods including molecular docking, molecular dynamics simulations, and density functional theory calculations, the complete covalent inhibition process of ebselen is simulated for the first time. Two possible pathways with different bound conformations of ebselen are identified. The hydrolysis of the enzyme‐ebselen adduct is found to be the rate‐determining step. The simulation results show that the behavior of water molecules at the hydrolysis site is crucial to distinguish the two paths energetically. Our simulations, which are in agreement with existing experimental results, provide a theoretical basis for the rational design and mechanism exploration of ebselen‐based inhibitors.