Decoding SARS‐CoV‐2 Inhibition: Insights From Molecular Dynamics Simulation of Condensed Amino Thiourea Scaffold Small Molecules

The main protease (M^pro) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) plays a crucial role in viral replication. In this study, the binding modes and inhibitory mechanisms of eight condensed amino thiourea scaffold inhibitors of M^pro in proteins were investigated using a combination of molecular docking, molecular dynamics simulations, and MM/PBSA binding free energy calculations. The results indicated that the para-hydroxyl group on the benzene ring at the head of the inhibitor has a decisive influence on the initial docking pose and binding free energy strength of the inhibitor. Additionally, the position and length of the hydrophobic side chain on the tail six-membered ring significantly impacted the final binding pose of the inhibitor. The presence of a long hydrophobic side chain in the ortho position of this ring, through its interaction with the P4 hydrophobic pocket, led to an opposite binding mode in the protein compared with when it was present with or without the para-side chain. Different lengths of para-substituted side chains affected the positioning of the inhibitors in the enzyme. These different binding modes led to variations in the binding free energy between the inhibitor and the protein, which in turn gave rise to differences in inhibitory capability.