High throughput virtual screening reveals SARS-CoV-2 multi-target binding natural compounds to lead instant therapy for COVID-19 treatment

Abstract

The present-day world is severely suffering from the recently emerged SARS-CoV-2. The lack of prescribed drugs for the deadly virus has stressed the likely need to identify novel inhibitors to alleviate and stop the pandemic. In the present high throughput virtual screening study, we used in silico techniques like receptor-ligand docking, Molecular dynamic (MD), and ADME properties to screen natural compounds. It has been documented that many natural compounds display antiviral activities, including anti-SARS-CoV effect. The present study deals with compounds of Natural Product Activity and Species Source (NPASS) database with known biological activity that probably impedes the activity of six essential enzymes of the virus. Promising drug-like compounds were identified, demonstrating better docking score and binding energy for each druggable targets. After an extensive screening analysis, three novel multi-target natural compounds were predicted to subdue the activity of three/more major drug targets simultaneously. Concerning the utility of natural compounds in the formulation of many therapies, we propose these compounds as excellent lead candidates for the development of therapeutic drugs against SARS-CoV-2.

Keywords: COVID-19; Molecular docking; Molecular dynamics; Muti-target; Natural compounds.

Fig. 1

Showing the chemical formula of reference/control ligand for each target protein.

Fig. 2

(A). Showing the contacts between multi-target NPASS compound, NPC214620 with (1) Endoribonuclease (2) Exoribonuclease (3) RNA dependent RNA polymerase (RdRp) (4) Methyltransferase and (5) 3C-like proteinase. The ligand 2D representation in the side panel is showing the rotatable bonds of the ligand in different colors. (B). Showing the contacts between multi-target NPASS compound, NPC52382 with (1) Helicase (2) Endoribonuclease (3) Exoribonuclease (4) Methyltransferase. The ligand 2D representation in the side panel is showing the rotatable bonds of the ligand in different colors. (C). Showing the contacts between multi-target NPASS compound, NPC270578 with (1) Helicase (2) Exoribonuclease (3) Methyltransferase. The ligand 2D representation in the side panel is showing the rotatable bonds of the ligand in different colors.

Fig. 2

(A). Showing the contacts between multi-target NPASS compound, NPC214620 with (1) Endoribonuclease (2) Exoribonuclease (3) RNA dependent RNA polymerase (RdRp) (4) Methyltransferase and (5) 3C-like proteinase. The ligand 2D representation in the side panel is showing the rotatable bonds of the ligand in different colors. (B). Showing the contacts between multi-target NPASS compound, NPC52382 with (1) Helicase (2) Endoribonuclease (3) Exoribonuclease (4) Methyltransferase. The ligand 2D representation in the side panel is showing the rotatable bonds of the ligand in different colors. (C). Showing the contacts between multi-target NPASS compound, NPC270578 with (1) Helicase (2) Exoribonuclease (3) Methyltransferase. The ligand 2D representation in the side panel is showing the rotatable bonds of the ligand in different colors.

Fig. 2

(A). Showing the contacts between multi-target NPASS compound, NPC214620 with (1) Endoribonuclease (2) Exoribonuclease (3) RNA dependent RNA polymerase (RdRp) (4) Methyltransferase and (5) 3C-like proteinase. The ligand 2D representation in the side panel is showing the rotatable bonds of the ligand in different colors. (B). Showing the contacts between multi-target NPASS compound, NPC52382 with (1) Helicase (2) Endoribonuclease (3) Exoribonuclease (4) Methyltransferase. The ligand 2D representation in the side panel is showing the rotatable bonds of the ligand in different colors. (C). Showing the contacts between multi-target NPASS compound, NPC270578 with (1) Helicase (2) Exoribonuclease (3) Methyltransferase. The ligand 2D representation in the side panel is showing the rotatable bonds of the ligand in different colors.

Fig. 2

(A). Showing the contacts between multi-target NPASS compound, NPC214620 with (1) Endoribonuclease (2) Exoribonuclease (3) RNA dependent RNA polymerase (RdRp) (4) Methyltransferase and (5) 3C-like proteinase. The ligand 2D representation in the side panel is showing the rotatable bonds of the ligand in different colors. (B). Showing the contacts between multi-target NPASS compound, NPC52382 with (1) Helicase (2) Endoribonuclease (3) Exoribonuclease (4) Methyltransferase. The ligand 2D representation in the side panel is showing the rotatable bonds of the ligand in different colors. (C). Showing the contacts between multi-target NPASS compound, NPC270578 with (1) Helicase (2) Exoribonuclease (3) Methyltransferase. The ligand 2D representation in the side panel is showing the rotatable bonds of the ligand in different colors.

Fig. 3

SP and XP docking validation and representation of both actives and decoys compounds by plotting the ROC curve.

Fig. 4

Molecular dynamics simulation. (A) and (B) showing the RMSD and RMSF plot of Exoribonuclease and NPC214620 complex (C) and (D) representing the RMSD and RMSF of Methyltransferase and NPC52382 complex whereas (E) and (F) showing the RMSD and RMSF of Helicase and NPC270578 complex, respectively. The blue and red lines in the background of the RMSF plot showing the beta and alpha helices, respectively.

Fig. 5

Graphical representation of protein-ligand contacts. (A) Showing the interaction between the helicase and NPC270578 (B), showing the interaction between Exoribonuclease and NPC214620, whereas (C) showing the interaction between Methyltransferase and NPC52382 compound.