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.