Simultaneously, the total number of H-bonds present in the protein was found to be stable during the simulation period, as shown in figure , with an average number of the total H-bonds of 924 (in the protein dimer). The per-residue Root Mean Square Fluctuations A redocking experiment is essential in testing the docking protocol quality, as such the co-crystallized ligand O6K was retrieved from the crystal structure of M pro (PDB ID: 6Y2G) and docked to the protein dimer. PyMOL software was utilized to superpose the docked complex to the solved structure. The root-mean-square displacement (RMSD) between the complex and the solved structure was 0.899 Å, where the number of fitted atoms was 1437, indicating high structural similarities. Figure shows the average binding affinities calculated utilizing five different conformations of the M pro after the 100 ns MD simulation. The error bars represent the standard deviation. The positive controls (O6K and N3) are shown in red columns, while the best two compounds (batzelladines H-I, 8-9) are in green. Additionally, Figure displays the hydrophobic contacts (dashed-gray lines), which represent the interactions established between the ligands (orange sticks) and the M pro residues (blue sticks). As reflected from figure , the average binding energies for most of the compounds under investigation are in good agreement with the positive controls, with compound 10 (batzelladine K) as an exception having a significantly low affinity against the M pro active site (-5.46 ±0.30 kcal/mol). For the rest of the compounds, the average binding energies ranged from -7.12 ±0.60 (8) down to -6.22 ±0.37 kcal/mol, while for the positive control, binding energies were found to be -7.36 ±0.34 kcal/mol and -6.36 ±0.31 kcal/mol for O6K and N3, respectively. The established interactions upon docking to the best representative complexes (having near average binding energy values) are listed in Table . Notably, the hydrophobic contact is the most reported interaction type, with few H-bonds formed in some complexes. For example, the O6K-M pro complex formed the highest number of interactions, represented by eight hydrophobic contacts and 4 H-bonds. Concurrently with figure , the O6K-M pro complex reported the lowest average binding energy value (-7.36 ±0.34 kcal/mol). On the other hand, the 10-M pro complex showed the highest (worst) average binding energy value (-5.46 ±0.30 kcal/mol) and has only four hydrophobic contacts. The two complexes 8-M pro and 9-M pro are amongst the compounds of the highest number of formed interactions, showing 6 and 7 hydrophobic contacts, corresponding to their average binding energy values (-7.12 ±0.60 and -7.0 ±0.28 kcal/mol, respectively).