3CL protease (3CLpro) is the main protease (Mpro) found in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which cuts the coronavirus polyprotein at eleven conserved sites and is essential for the virus replication. Therefore, 3CLpro has been widely used as a promising drug target. Many small-molecule drug candidates targeting 3CLpro have been proposed to inhibit the virus replication. In this work, we aim to reveal detailed interactions between ten small candidate molecules with extensive attention and 3CLpro using molecular docking and molecular dynamics simulations. First, we identified the possible binding sites of these candidate molecules on 3CLpro via molecular docking. Then, a series of 100 ns all-atom molecular dynamics simulations of strongest binding modes were performed to further evaluate the dynamical interactions between the molecules and 3CLpro in detail. Last, the binding free energy of these molecules on 3CLpro was calculated using MM/PBSA calculation, where the contribution of key amino acids was highlighted. The binding kinetics revealed in this work may provide useful insights into the action mechanism and applicability of these small-molecule drug candidates.
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