Molecular docking simulation and Ligand(s) –TMPRSS2 binding
TMPRSS2 is the serine protease, which mediates the S-protein of SARS-CoV-2 for the virus entry through the ACE2 enzyme. Reportedly, by inhibiting the TMPRSS2 protease, the SARS-CoV-2 fusion can be stopped[13-17]. In TMPRSS2, the ligand-binding active site has catalytic triad consists of Ser186, His41, and Asp180 amino acids, to inhibit the function of this enzyme, ligands should mainly bind with these key amino acids. The molecular docking simulations for the drug molecules casmostat, nafamostat and leupeptin with TMPRSS2 have been performed using induced fit docking (IFD) method, the docking score values of the three molecules are -6.648, -7.075 and -9.325 kcal/mol respectively, whereas the IFD scores are -490.01, -493.20 and -501.23 kcal/mol. And the glide energy values -57.457, -56.96 and -64.35 kcal/mol (Table 1). On compare the above-said values reveal that, consistently, leupeptin exhibits high values. The magnitude of difference in docking scores and glide energy reflects the nature of their intermolecular interactions with the neighboring amino acids present in the active site of TMPRSS2 protease (Figure 2). In the catalytic site, the camostat and leupeptin are forming strong interactions with Asp180, Ser186 and His41 than the nafamostat(Table 2); however, the interactions of leupeptin with the catalytic amino acids Asp180, Ser186 and His41are found stronger and the interaction distances are 1.9, 2.1, 2.0 and 3.5 Å respectively.Figure 3 shows the superimposed form of the three drug molecules in the active site of TMPRSS2, reveal the orientation of the molecules and the difference. From this, we observed that the three molecules have a tendency to bind with the serine 2 protease TMPRSS2. However, the nafamostat is lacking the Ser186 and His41 interactions with TMPRSS2 (Table 2). Further, we have probed the existence of these interactions, stability, and the binding affinity of the three drug molecules with the TMPRSS2 during the molecular dynamics simulations.