Potential inhibitors of SARS-CoV-2 (COVID 19) proteases PLpro and Mpro/ 3CLpro: molecular docking and simulation studies of three pertinent medicinal plant natural components

Abstract

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - coronavirus disease 2019 (COVID-19) has raised a severe global public health issue and creates a pandemic situation. The present work aims to study the molecular -docking and dynamic of three pertinent medicinal plants i.e. Eurycoma harmandiana, Sophora flavescens and Andrographis paniculata phyto-compounds against SARS-COV-2 papain-like protease (PL^pro) and main protease (M^pro)/3-chymotrypsin-like protease (3CL^pro). The interaction of protein targets and ligands was performed through AutoDock-Vina visualized using PyMOL and BIOVIA-Discovery Studio 2020. Molecular docking with canthin-6-one 9-O-beta-glucopyranoside showed highest binding affinity and less binding energy with both PL^pro and M^pro/3CL^pro proteases and was subjected to molecular dynamic (MD) simulations for a period of 100ns. Stability of the protein-ligand complexes was evaluated by different analyses. The binding free energy calculated using MM-PBSA and the results showed that the molecule must have stable interactions with the protein binding site. ADMET analysis of the compounds suggested that it is having drug-like properties like high gastrointestinal (GI) absorption, no blood-brain barrier permeability and high lipophilicity. The outcome revealed that canthin-6-one 9-O-beta-glucopyranoside can be used as a potential natural drug against COVID-19 protease.

Keywords: Canthin-6-one 9-O-Beta-glucopyranoside; Molecular dynamics; Natural inhibitor; PLpro-Mpro/3CLpro; SARS-CoV-2 (COVID-19).

Graphical abstract

Fig. 1

Interactions established after docking the secondary metabolite against SARS-CoV-2 PL^pro Protein (6W9C). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 1

Interactions established after docking the secondary metabolite against SARS-CoV-2 PL^pro Protein (6W9C). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 1

Interactions established after docking the secondary metabolite against SARS-CoV-2 PL^pro Protein (6W9C). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 1

Interactions established after docking the secondary metabolite against SARS-CoV-2 PL^pro Protein (6W9C). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 1

Interactions established after docking the secondary metabolite against SARS-CoV-2 PL^pro Protein (6W9C). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 1

Interactions established after docking the secondary metabolite against SARS-CoV-2 PL^pro Protein (6W9C). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 1

Interactions established after docking the secondary metabolite against SARS-CoV-2 PL^pro Protein (6W9C). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 2

Interactions established after docking the secondary metabolite against SARS-CoV-2 M^pro/3CL^pro Protein (6M2N). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 2

Interactions established after docking the secondary metabolite against SARS-CoV-2 M^pro/3CL^pro Protein (6M2N). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 2

Interactions established after docking the secondary metabolite against SARS-CoV-2 M^pro/3CL^pro Protein (6M2N). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 2

Interactions established after docking the secondary metabolite against SARS-CoV-2 M^pro/3CL^pro Protein (6M2N). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 2

Interactions established after docking the secondary metabolite against SARS-CoV-2 M^pro/3CL^pro Protein (6M2N). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 2

Interactions established after docking the secondary metabolite against SARS-CoV-2 M^pro/3CL^pro Protein (6M2N). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 2

Interactions established after docking the secondary metabolite against SARS-CoV-2 M^pro/3CL^pro Protein (6M2N). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted line represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 3

Interactions established after docking the drugs against SARS-CoV-2 PL^pro protein (6W9C). The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted lined represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 3

Interactions established after docking the drugs against SARS-CoV-2 PL^pro protein (6W9C). The receptor-ligand interaction is represented on a 3D diagram (Right) and 2D diagram (Left). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted lined represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 4

Interactions established after docking the drugs against SARS-CoV-2 M^pro/3CL^pro Protein (6M2N). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (right) and 2D diagram (left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted lined represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 4

Interactions established after docking the drugs against SARS-CoV-2 M^pro/3CL^pro Protein (6M2N). The interacting residues of the protein are labeled in purple and the docking scores are listed under each of the complex, respectively. The receptor-ligand interaction is represented on a 3D diagram (right) and 2D diagram (left). Drugs are in cyan and interacting atoms of protein are represented red in the diagram, while green dotted lines represent the conventional h-bond interactions, light green dotted lined represents weak van der Waals interactions. Additionally, dotted lines in sky blue display the pi-donor hydrogen bond, pi-sigma interaction is shown as violet dashed lines, pink dotted lines show alkyl and pi-alkyl interactions, respectively.

Fig. 5

Comparative binding energy of canthin-6-one 9-O-beta-glucopyranoside with M^pro/3CL^pro and PL^pro (∗energy values are the smaller in M^pro/3CL^pro and PL^pro in respective time scale).

Fig. 6

Comparative RMSD vs. binding energy plots of canthin-6-One 9-O-beta-Glucopyranoside bound with M^pro/3CL^pro and PL^pro calculated from MD simulation trajectory.

Fig. 7

Plot showing MM-PBSA calculation of canthin-6-One 9-O-beta-Glucopyranoside bound with M^pro/3CL^pro (black) and PL^pro (red) calculated from MD simulation trajectory.