The monomeric form of the E protein structure was obtained from the hexameric 1.9 Å resolution X-ray structure (PDB ID: 7K3G). The binding poses of ligands to the E protein opening were explored using Autodock Vina 1.5.6 software. For each protocol, 10 poses were generated for all four enzyme-substrate complexes, with an exhaustiveness value of 20. To perform the MD simulations, the GROMACS-4.5.6 program was utilized, along with the AMBER03 force field. The simulations were performed in a cubic box filled with TIP3P water molecules, and the system was neutralized by replacing some water molecules with potassium and chloride ions to simulate a physiological ion concentration of 0.154 M. The MD simulations were performed for 200 ns. The SETTLE algorithm was used to constrain the bond lengths and angles of the water molecules, and the LINCS algorithm was employed to constrain the remaining bond lengths. The simulations were carried out in NPT ensembles with constant N, P, and T.