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. 2021 Nov;39(18):7017-7034.
doi: 10.1080/07391102.2020.1804457. Epub 2020 Aug 27.

In silico screening of hundred phytocompounds of ten medicinal plants as potential inhibitors of nucleocapsid phosphoprotein of COVID-19: an approach to prevent virus assembly

Rajan Rolta  1 , Rohitash Yadav  2 , Deeksha Salaria  1 , Shubham Trivedi  3 , Mohammad Imran  4 , Anuradha Sourirajan  1 , David J Baumler  5 , Kamal Dev  1
Affiliations

In silico screening of hundred phytocompounds of ten medicinal plants as potential inhibitors of nucleocapsid phosphoprotein of COVID-19: an approach to prevent virus assembly

Rajan Rolta et al. J Biomol Struct Dyn. 2021 Nov.

Abstract

Currently, there is no specific treatment to cure COVID-19. Many medicinal plants have antiviral, antioxidant, antibacterial, antifungal, anticancer, wound healing etc. Therefore, the aim of the current study was to screen for potent inhibitors of N-terminal domain (NTD) of nucleocapsid phosphoprotein of SARS-CoV-2. The structure of NTD of RNA binding domain of nucleocapsid phosphoprotein of SARS coronavirus 2 was retrieved from the Protein Data Bank (PDB 6VYO) and the structures of 100 different phytocompounds were retrieved from Pubchem. The receptor protein and ligands were prepared using Schrodinger's Protein Preparation Wizard. Molecular docking was done by using the Schrodinger's maestro 12.0 software. Drug likeness and toxicity of active phytocompounds was predicted by using Swiss adme, admetSAR and protox II online servers. Molecular dynamic simulation of the best three protein- ligand complexes (alizarin, aloe-emodin and anthrarufin) was performed to study the interaction stability. We have identified three potential active sites (named as A, B, C) on receptor protein for efficient binding of the phytocompounds. We found that, among 100 phytocompounds, emodin, aloe-emodin, anthrarufin, alizarine, and dantron of Rheum emodi showed good binding affinity at all the three active sites of RNA binding domain of nucleocapsid phosphoprotein of COVID-19.The binding energies of emodin, aloe-emodin, anthrarufin, alizarine, and dantron were -8.299, -8.508, -8.456, -8.441, and -8.322 Kcal mol-1 respectively (site A), -7.714, -6.433, -6.354, -6.598, and -6.99 Kcal mol-1 respectively (site B), and -8.299, 8.508, 8.538, 8.841, and 8.322 Kcal mol-1 respectively (site C). All the active phytocompounds follows the drug likeness properties, non-carcinogenic, and non-toxic. Theses phytocompounds (alone or in combination) could be developed into effective therapy against COVID-19. From MD simulation data, we found that all three complexes of 6VYO with alizarin, aloe-emodin and anthrarufin were stable up to 50 ns. These phytocompounds can be tested further for in vitro or in vivo and used as a potential drug to cure SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.

Keywords: Active site prediction and MD simulation; COVID-19; Molecular docking; Phytocompounds; RNA binding domain of nucleocapsid phosphoprotein; antiviral and toxicity.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1.
Figure 1.
Proposed Binding mechanism of phytocompounds with NTD of nucleocapsid protein RNA binding protein of COVID-19 (Prepared using BioRender).
Figure 2.
Figure 2.
Schematic of the experiments followed in the current study.
Figure 3.
Figure 3.
(A) Secondary structure of NTD (amino acid residues 50-173) of RNA binding domain of nucleocapsid phosphoprotein from SARS coronavirus 2 (PDB ID: 6VYO); (B) Topology of secondary structure; and C) The Ramachandran plot describes the favored and disfavored regions of residues. The maximum (92.5%) residues are located in an allowed region.
Figure 4.
Figure 4.
(A) Conserved domains of (6 VYO_1) chains A, B, C, D nucleoprotein of Severe acute respiratory syndrome coronavirus 2. (B) List of domain hits with E-values.
Figure 5.
Figure 5.
Active site prediction. 3-D structure representation of tetrameric RNA binding domain (N-terminal domain) of nucleocapsid phosphoprotein from SARS coronavirus 2 (PDB ID: 6VYO) showing three predicted binding sites shown as Active site A, Active site B and Active site C (A). Panel B, C, and D represent tetrameric RNA binding domain showing each active site as indicated.
Figure 6.
Figure 6.
Structures of potential phytocompounds of R. emodi: A) Anthrarufin, (B) Aloe- emodin, (C) Alizarine, (D) Dantron, (E) Emodin.
Figure 7.
Figure 7.
The 2D molecular interactions of best 5 phytocompounds with active site A of 6VYO: (A) Alizarin, (B) Aloe- emodin, (C) Anthrarufin (D), Dantron, (E) Emodin.
Figure 8.
Figure 8.
Surface view of 6VYO (active site A) complex with best 5 compounds of selected medicinal plants: (A) Alizarin, (B) Aloe- emodin, (C) Anthrarufin (D), Dantron, (E) Emodin. Phytocompounds are colored in green.
Figure 9.
Figure 9.
The 2 D molecular interactions of best 5 phytocompounds with active site B of 6VYO: (A) Alizarin, (B) Aloe- emodin, (C) Anthrarufin (D) Dantron (E) Emodin.
Figure 10.
Figure 10.
Surface of 6VYO (active site B) with best 5 compounds: (A) Alizarin, (B) Aloe- emodin, (C) Anthrarufin (D) Dantron (E) Emodi. Phytocompounds are colored in green.
Figure 11.
Figure 11.
The 2 D molecular interactions of best 5 phytocompounds with active site C of 6VYO: (A) Alizarin, (B) Aloe- emodin, (C) Anthrarufin (D) Dantron (E) Emodin. Phytocompounds are colored in green.
Figure 12.
Figure 12.
Surface of 6VYO (active site C) and 5 best compounds complex: (A) Alizarin, (B) Aloe-emodin, (C) Anthrarufin (D) Dantron (E) Emodin. Phytocompounds are colored in green.
Figure 13.
Figure 13.
A) RMSD graph of three protein-ligand complexes for 50 ns. (B) RMSF graph of three ligand-protein complexes for 50 ns.
Figure 14.
Figure 14.
(A) Number of Intermolecular hydrogen bonds between the ligands and amino acid residues of the target protein for 50 ns. (B) Radius of gyration (RoG) results of the ligand-protein complex for 50 ns.
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