Identification of doxorubicin as a potential therapeutic against SARS-CoV-2 (COVID-19) protease: a molecular docking and dynamics simulation studies

Abstract

After one year, the COVID-19 pandemic caused by SARS-CoV-2 is still the largest concern for the scientific community. Of the many recognized drug targets of SARS-CoV-2, the main protease is one of the most important target due to its function in viral replication. We conducted an in silico study with repurposing drugs of antibiotics class against virus protease and peptidase using AutoDock tool. The following significant binding energy interaction was observed with protease (PDB: 6LU7) like piperacillin -7.25; tobramycin -9.20 and doxorubicin (Doxo) -10.04 kcal/mol and with peptidase (PDB: 2GTB) piperacillin -7.08; tobramycin -8.54 and Doxo -9.89 kcal/mol. Furthermore, the interaction and stability behavior of the Doxo-protease and Doxo-peptidase complexes were analyzed for a 100-nanosecond (ns) time. Calculated RMSD values observed using molecular dynamics simulation (MDS) were found to be 0.15-0.25 nm, RMSF calculation per residues showed a value near 0.2 nm and R_g values remained approximately 2.25 nm. MM-PBSA analysis of total binding energy calculation of Doxo-protease and Doxo-peptidase complexes are found to be -148.692 and -105.367 kJ/mol, respectively. Moreover, amino acid residue ASP-197 showed the lowest contribution binding energy i.e. -18.1185 kJ/mol, and amino acid residue ASP-187 showed -17.0267 kJ/mol contribution energy. Thus, significant docking interaction and stable dynamicity of Doxo-protease complex with time was suggested that Doxo could be a choice to inhibit potentially the viral proteases that could prevent the entry inside the host cell to control the COVID-19 disease. Communicated by Ramaswamy H. Sarma.

Keywords: Doxorubicin; MDS; SARS-CoV-2; antiviral drugs; protease inhibitor.

Figure 1.

(a) The 3D crystal structure of COVID-19 main protease in complex with an inhibitor N3 (PDB: 6LU7) (Jin et al., 2020) and (b) 3D crystal structure of SARS coronavirus main peptidase (PDB: 2GTB) (with an additional Ala at the N-terminus of each protomer) inhibited by an aza-peptide epoxide (Lee et al., 2007).

Figure 2.

(a,b) Piperacillin, (c,d) tobramycin, (e,f) Doxo (shown by gray color in the sphere with stick pattern) interaction with Covid-19 main protease [shown by rainbow color ribbon pattern (in figures a, c and f)] (PDB: 6LU7). In figures(b, d, e), the surrounding amino acid residues involved in hydrophobic interaction are shown within spheres. Green color dotted lines show the formation of hydrogen bonds. 3D and 2D graphics were generated by Discovery Studio Visualizer 2019.

Figure 3.

3D visualization of the binding site of Doxo (in center gray color stick pattern) and interaction with main protease (PDB: 6LU7). Interacting close amino acid residues (shown in blue color with stick pattern) of the binding pocket.

Figure 4.

(a,b) Piperacillin, (c,d) tobramycin, (e,f) Doxo (shown by gray color in the sphere with stick pattern) interaction with peptidase [shown by rainbow color ribbon pattern (in figures a, c and f)] (PDB: 6LU7). In figures (b,d,e), the surrounding amino acid residues involved in hydrophobic interaction are shown within spheres. Green color dotted lines show the formation of hydrogen bonds. 3D and 2D graphics were generated by Discovery Studio Visualizer 2019.

Figure 5.

3D visualization of the binding site of Doxo (in center gray color stick pattern) and interaction with peptidase (PDB: 2GTB). Interacting close amino acid residues (shown in blue color with stick pattern) of the binding pocket.

Figure 6.

Graphical representation (a) RMSD plot of Main protease (Black color), Doxo–protease (red color) and Doxo–peptidase (blue color) and showing deviation and stability during 100 ns period. (b) RMSF plot with fluctuation per residues. (c) Hydrogen bond plot showing formation hydrogen bonds during 100,000 ps period. (d) Radius of gyration (R_g) plot showing compactness of protease, Doxo–protease and Doxo–peptidase molecule during 100,000 ps simulation, where nm = nanometer; ns = nanosecond; ps = picosecond.

Figure 7.

Graph plot showing total predicted MM-PBSA binding energy (kJ/mol) of Doxo–protease (green color) and Doxo–peptidase (blue color) complex interaction during 100,000 ps (100 ns) simulation.

Figure 8.

Graph plot showing calculated binding energy (kJ/mol) contributed by per residues of (a) protease (PDB: 6LU7) and (b) peptidase (PDB:2GTB) during interaction with Doxo.