Strong Binding of Leupeptin with TMPRSS2 Protease May Be an Alternative to Camostat and Nafamostat for SARS-CoV-2 Repurposed Drug: Evaluation from Molecular Docking and Molecular Dynamics Simulations

Abstract

The unprecedented coronavirus SARS-CoV-2 outbreak at Wuhan, China, caused acute respiratory infection to humans. There is no precise vaccine/therapeutic agents available to combat the COVID-19 disease. Some repurposed drugs are saving the life of diseased, but the complete cure is relatively less. Several drug targets have been reported to inhibit the SARS-CoV-2 virus infection, in that TMPRSS2 (transmembrane protease serine 2) is one of the potential targets; inhibiting this protease stops the virus entry into the host human cell. Camostat mesylate, nafamostat, and leupeptin are the drugs, in which the first two drugs are being used for COVID-19 and leupeptin also tested. To consider these drugs as the repurposed drug for COVID-19, it is essential to understand their binding affinity and stability with TMPRSS2. In the present study, we performed the molecular docking and molecular dynamics (MD) simulation of these molecules with the TMPRSS2. The docking study reveals that leupeptin molecule strongly binds with TMPRSS2 protein than the other two drug molecules. The RMSD and RMSF values of MD simulation confirm that leupeptin and the amino acids of TMPRSS2 are very stable than the other two molecules. Furthermore, leupeptin forms interactions with the key amino acids of TMPRSS2 and the same have been maintained during the MD simulations. This structural and dynamical information is useful to evaluate these drugs to be used as repurposed drugs, however, the strong binding profile of leupeptin with TMPRSS2, suggests, it may be considered as a repurposed drug for COVID-19 disease after clinical trial.

Keywords: Binding affinity; Molecular docking; Molecular dynamics; Repurposed drug; SARS-CoV-2; TMPRSS2.

Fig. 1

Chemical structure of the drug molecules

Fig. 2

Intermolecular interactions and planner (2D) view of ligands with active site residues of TMPRSS2 complexes. a Camostat mesylate. b Nafamostat. c Leupeptin

Fig. 3

Connolly surface map showing the superimpose of ligands in the active site environment of TMPRSS2. Camostat mesylate (green), nafamostat (pink), and leupeptin (cyan)

Fig. 4

RMSD of three ligand-TMPRSS2 complexes during the MD simulation

Fig. 5

RMSF of three ligand-TMPRSS2 complexes during the MD simulation

Fig. 6

Superimposed view of ligand-TMPRSS2 complexes from molecular docking and MD simulations

Fig. 7

Intermolecular interactions of (a) camostat mesylate, (b) nafamostat, and (c) leupeptin in the active site of TMPRSS2 at 100 ns of MD simulations

Fig. 8

Different types of intermolecular interactions and their stability during the MD simulation

Fig. 9

2D view of intermolecular interactions of three ligands—TMPRSS2 and their stability (%) during the MD simulations