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. 2022 Apr;40(6):2769-2784.
doi: 10.1080/07391102.2020.1842807. Epub 2020 Nov 5.

SARS-CoV-2 Mpro inhibitors: identification of anti-SARS-CoV-2 Mpro compounds from FDA approved drugs

Shiv Bharadwaj  1 , Esam Ibraheem Azhar  2   3 , Mohammad Amjad Kamal  4   5 , Leena Hussein Bajrai  3   6 , Amit Dubey  7 , Kanupriya Jha  8 , Umesh Yadava  9 , Sang Gu Kang  1 , Vivek Dhar Dwivedi  8
Affiliations

SARS-CoV-2 Mpro inhibitors: identification of anti-SARS-CoV-2 Mpro compounds from FDA approved drugs

Shiv Bharadwaj et al. J Biomol Struct Dyn. 2022 Apr.

Abstract

Recent outbreak of COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has raised serious global concern for public health. The viral main 3-chymotrypsin-like cysteine protease (Mpro), known to control coronavirus replication and essential for viral life cycle, has been established as an essential drug discovery target for SARS-CoV-2. Herein, we employed computationally screening of Druglib database containing FDA approved drugs against active pocket of SARS-CoV-2 Mpro using MTiopen screen web server, yields a total of 1051 FDA approved drugs with docking energy >-7 kcal/mol. The top 10 screened potential compounds against SARS-CoV-2 Mpro were then studied by re-docking, binding affinity, intermolecular interaction, and complex stability via 100 ns all atoms molecular dynamics (MD) simulation followed by post-simulation analysis, including end point binding free energy, essential dynamics, and residual correlation analysis against native crystal structure ligand N3 inhibitor. Based on comparative molecular simulation and interaction profiling of the screened drugs with SARS-CoV-2 Mpro revealed R428 (-10.5 kcal/mol), Teniposide (-9.8 kcal/mol), VS-5584 (-9.4 kcal/mol), and Setileuton (-8.5 kcal/mol) with stronger stability and affinity than other drugs and N3 inhibitor; and hence, these drugs are advocated for further validation using in vitro enzyme inhibition and in vivo studies against SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.

Keywords: COVID-19; drug repurposing; molecular docking; molecular dynamics simulation; structure-based virtual screening.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1.
Figure 1.
Repurposing of FDA approved drugs from Druglib database via MTiOpenScreen virtual screening web server against SARS-CoV-2 Mpro compounds.
Figure 2.
Figure 2.
List of screened top 10 FDA approved drugs against SARS-CoV-2 Mpro with 2D structural formula and molecular weight.
Figure 3.
Figure 3.
3D docked poses of screened drugs; (a) R428, (b) Etoposide, (c) MK-3207, (d) CEP-11981, (e) Teniposide, (f) Orvepitant, (g) VS-5584, (h) UK-432097, (i) Tadalafil, and (j) Setileuton, in the active pocket of SARS-CoV-2 Mpro.
Figure 4.
Figure 4.
Total molecular mechanics generalized born surface area (MM/GBSA) binding free energy (kcal/mol) values calculated for screened drugs, i.e. (a) R428, (b) Etoposide, (c) MK-3207, (d) CEP-11981, (e) Teniposide, (f) Orvepitant, (g) Vs-5584, (h) UK-432097, (i) Tadalafil, and (j) Setileuton, docked with SARS-CoV-2 Mpro.
Figure 5.
Figure 5.
3D poses extracted at the end of 100 ns MD simulation for the screened drugs, i.e. (a) R428, (b) Etoposide, (c) MK-3207, (d) CEP-11981, (e) Teniposide, (f) Orvepitant, (g) VS-5584, (h) UK-432097, (i) Tadalafil, and (j) Setileuton, docked with SARS-CoV-2 Mpro where protein surface is generated based on the nature of residue property and ligand color was computed based on the nature of atom in the structure.
Figure 6.
Figure 6.
RMSD values for alpha carbon atoms (violet color curves) of SARS-CoV-2 Mpro and selected ligands (red curves), viz. (a) R428, (b) Etoposide, (c) MK-3207, (d) CEP-11981, (e) Teniposide, (f) Orvepitant, (g) VS-5584, (h) UK-432097, (i) Tadalafil, and (j) Setileuton, were plotted with respect to 100 ns simulation time.
Figure 7.
Figure 7.
Protein-ligand interactions mapping recorded for the screened drugs; (a) R428, (b) Etoposide, (c) MK-3207, (d) CEP-11981, (e) Teniposide, (f) Orvepitant, (g) VS-5584, (h) UK-432097, (i) Tadalafil, and (j) Setileuton, with SARS-CoV-2 Mpro were extracted from 100 ns MD simulations.
Figure 8.
Figure 8.
End point binding free energy (kcal/mol) values calculated for snapshots extracted for SARS-CoV-2 Mpro docked with screened drugs, i.e. (a) R428, (b) Etoposide, (c) MK-3207, (d) CEP-11981, (e) Teniposide, (f) Orvepitant, (g) VS-5584, (h) UK-432097, (i) Tadalafil, and (j) Setileuton, from respective 100 ns MD simulation trajectories.
Figure 9.
Figure 9.
Principal component analysis of MD simulation trajectories for SARS-CoV-2 Mpro docked with (a) R428, (b) Etoposide, (c) MK-3207, (d) CEP-11981, (e) Teniposide, (f) Orvepitant, (g) VS-5584, (h) UK-432097, (i) Tadalafil, and (j) Setileuton. Herein, continuous color changes from blue to white to red exhibit periodic jumps between structural conformations extracted from 100 ns simulation trajectories.
Figure 10.
Figure 10.
Dynamic cross-correlation matrix analysis for SARS-CoV-2 Mpro complexed with screened FDA approved drugs, i.e. (a) R428, (b) Etoposide, (c) MK-3207, (d) CEP-11981, (e) Teniposide, (f) Orvepitant, (g) VS-5584, (h) UK-432097, (i) Tadalafil, and (j) Setileuton. Herein, cyan color explains positive correlation and cyan red signifies the negative correlation in the movement of residues during the course of 100 ns simulation interval.
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