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In this study, the interactions between the inhibitors and the main protease (Mpro) of SARS-CoV-2 were studied, to understand how the inhibitors influence the dynamics of Mpro of SARS-CoV-2. Firstly, molecular docking was applied to obtain the binding complex of the inhibitors and the main protease, and the binding affinities. The classical molecular dynamics simulations show that, all the tested inhibitors cannot inhibit the dynamics of Mpro’s active pocket. The replica-exchange molecular dynamics simulations show that, the inhibitors influence the shape of the active pocket of Mpro. With the formation of hydrogen bonds between the inhibitors and different sites of the active pocket, the inhibitors affect the length and width of the pocket. The study indicates that the drug design of Mpro should fully consider the importance of the hydrogen network between the potential inhibitors and the active pocket. In this study, the interactions between the inhibitors and the main protease (Mpro) of SARS-CoV-2 were studied, to understand how the inhibitors influence the dynamics of Mpro of SARS-CoV-2. Firstly, molecular docking was applied to obtain the binding complex of the inhibitors and the main protease, and the binding affinities. The classical molecular dynamics simulations show that, all the tested inhibitors cannot inhibit the dynamics of Mpro’s active pocket. The replica-exchange molecular dynamics simulations show that, the inhibitors influence the shape of the active pocket of Mpro. With the formation of hydrogen bonds between the inhibitors and different sites of the active pocket, the inhibitors affect the length and width of the pocket. The study indicates that the drug design of Mpro should fully consider the importance of the hydrogen network between the potential inhibitors and the active pocket. [ABSTRACT FROM AUTHOR]