In Silico Exploration of Phytoconstituents From Phyllanthus emblica and Aegle marmelos as Potential Therapeutics Against SARS-CoV-2 RdRp

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has increased the importance of computational tools to design a drug or vaccine in reduced time with minimum risk. Earlier studies have emphasized the important role of RNA-dependent RNA polymerase (RdRp) in SARS-CoV-2 replication as a potential drug target. In our study, comprehensive computational approaches were applied to identify potential compounds targeting RdRp of SARS-CoV-2. To study the binding affinity and stability of the phytocompounds from Phyllanthus emblica and Aegel marmelos within the defined binding site of SARS-CoV-2 RdRp, they were subjected to molecular docking, 100 ns molecular dynamics (MD) simulation followed by post-simulation analysis. Furthermore, to assess the importance of features involved in the strong binding affinity, molecular field-based similarity analysis was performed. Based on comparative molecular docking and simulation studies of the selected phytocompounds with SARS-CoV-2 RdRp revealed that EBDGp possesses a stronger binding affinity (-23.32 kcal/mol) and stability than other phytocompounds and reference compound, Remdesivir (-19.36 kcal/mol). Molecular field-based similarity profiling has supported our study in the validation of the importance of the presence of hydroxyl groups in EBDGp, involved in increasing its binding affinity toward SARS-CoV-2 RdRp. Molecular docking and dynamic simulation results confirmed that EBDGp has better inhibitory potential than Remdesivir and can be an effective novel drug for SARS-CoV-2 RdRp. Furthermore, binding free energy calculations confirmed the higher stability of the SARS-CoV-2 RdRp-EBDGp complex. These results suggest that the EBDGp compound may emerge as a promising drug against SARS-CoV-2 and hence requires further experimental validation.

Keywords: Aegle marmelos SARS-CoV-2 RdRp; MD simulation; Phyllanthus emblica; drug repurposing; molecular docking.

Figure 1.

The defined binding pocket of SARS-CoV-2-RdRp (PDB ID: 7C2K). The complex of RdRp (Teal), NSP 8 (Purple), NSP 7 (Yellow), and RNA (Orange) represented with molecular surface and the active site of RdRp shown by CPK representation. NSP indicates non-structural proteins; PDB, Protein Data Bank; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RdRp, RNA-dependent RNA polymerase.

Figure 2.

Binding interaction of (A) Remdesivir and (B) EBDGp with SARS-CoV-2 RdRp. Interacting residues are represented in lines and ligand shown in the ball and stick model. Hydrogen bonds are represented by black dashed lines. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2; RdRp, RNA-dependent RNA polymerase.

Figure 3.

Binding interaction of (A) Marmelide and (B) Seselin with SARS-CoV-2 RdRp. Interacting residues are represented in lines and ligand shown in the ball and stick model. Hydrogen bonds and π-cation are black and green colored dashed lines, respectively. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2; RdRp, RNA-dependent RNA polymerase.

Figure 4.

Binding interaction of (A) Pedunculagin and (B) Chebulagic acid with SARS-CoV-2 RdRp. Interacting residues are represented in lines and ligand shown in the ball and stick model. Hydrogen bonds, salt bridge, and π-cation are black, pink, and green colored dashed lines, respectively. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2; RdRp, RNA-dependent RNA polymerase.

Figure 5.

Plots of RMSD of (A) SARS-CoV-2-RdRp C-alpha atoms and (B) lead compounds along with Remdesivir during 100 ns MD simulation time. MD indicates molecular dynamics; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RdRp, RNA-dependent RNA polymerase; RMSD, root mean square deviation.

Figure 6.

RMSF profiles of the SARS-CoV-2 RdRp complexed with Remdesivir and lead compounds in the entire 100 ns MD simulation. MD indicates molecular dynamics; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RdRp, RNA-dependent RNA polymerase; RMSF, root mean square fluctuation.

Figure 7.

SARS-CoV-2-RdRp interactions profile with (A) Remdesivir, (B) EBDGp, and (C) Marmelide during 100 ns simulation. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2; RdRp, RNA-dependent RNA polymerase.

Figure 8.

SARS-CoV-2-RdRp interactions profile with (A) Seselin, (B) Pedunculagin, and (C) Chebulagic acid during 100 ns simulation. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2; RdRp, RNA-dependent RNA polymerase.

Figure 9.

Hydrogen bonding profile of SARS-CoV-2 RdRp with (A) Remdesivir, (B) EBDGp, (C) Marmelide, (D) Seselin, (E) Pedunculagin, and (F) Chebulagic acid during 100 ns simulation. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2; RdRp, RNA-dependent RNA polymerase.

Figure 10.

The ensemble-averaged Prime binding free energies in kcal/mol of docked complexes during the 100 ns MD simulation. MD indicates molecular dynamics; MM/GBSA, molecular mechanics generalized born and surface area.

Figure 11.

Field-based template aligned structures of Remdesivir and EBDGp. Field points color coding: negative electrostatic field, blue; positive electrostatic field, red; van der Waal (VDW) surface, yellow; hydrophobic field, orange.