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. 2023 Jan 5:13:1073419.
doi: 10.3389/fmicb.2022.1073419. eCollection 2022.

Targeting envelope proteins of poxviruses to repurpose phytochemicals against monkeypox: An in silico investigation

Pallavi Gulati  1 , Jatin Chadha  2 , Kusum Harjai  2 , Sandeepa Singh  3
Affiliations

Targeting envelope proteins of poxviruses to repurpose phytochemicals against monkeypox: An in silico investigation

Pallavi Gulati et al. Front Microbiol. .

Abstract

The monkeypox virus (MPXV) has become a major threat due to the increasing global caseload and the ongoing multi-country outbreak in non-endemic territories. Due to limited research in this avenue and the lack of intervention strategies, the present study was aimed to virtually screen bioactive phytochemicals against envelope proteins of MPXV via rigorous computational approaches. Molecular docking, molecular dynamic (MD) simulations, and MM/PBSA analysis were used to investigate the binding affinity of 12 phytochemicals against three envelope proteins of MPXV, viz., D13, A26, and H3. Silibinin, oleanolic acid, and ursolic acid were computationally identified as potential phytochemicals that showed strong binding affinity toward all the tested structural proteins of MPXV through molecular docking. The stability of the docked complexes was also confirmed by MD simulations and MM/PBSA calculations. Results from the iMODS server also complemented the findings from molecular docking and MD simulations. ADME analysis also computationally confirmed the drug-like properties of the phytochemicals, thereby asserting their suitability for consumption. Hence, this study envisions the candidature of bioactive phytochemicals as promising inhibitors against the envelope proteins of the MPXV, serving as template molecules that could further be experimentally evaluated for their efficacy against monkeypox.

Keywords: bioactive phytochemicals; drug repurposing; envelope proteins; molecular docking; molecular simulation; monkeypox virus; poxviruses.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Crystal structures of envelope proteins of MPXV. (A) D13 protein trimer (PDB ID: 6BED), (B) A26 protein (PDB ID: 6A9S), (C) H3 protein (PDB ID: 5EJ0). The structures were retrieved from the PDB online server (www.rcsb.org).
Figure 2
Figure 2
Bar graph depicting the binding energies of different phytochemicals docked against D13, A26, and H3 envelope proteins of MPXV. Rifampicin was used as a control.
Figure 3
Figure 3
Molecular docking of silibinin, oleanolic acid, and ursolic acid against the D13 protein (PDB ID: 6BED). Left Panel: Visualization of the binding position of the ligand within the protein cavity. Central Panel: Ribbon diagram showing the docked complex. Ligands have been shown in red. Right Panel: 2D diagram representing the interactions between the phytochemicals and D13 protein generated by LigPlot. Dashed lines show hydrogen bonds while the red arcs represent hydrophobic interactions. Rifampicin has been used as a control. Docking was performed via AutoDock Vina (Version 1.5.7) and the 3D structures were visualized using PyMol tool.
Figure 4
Figure 4
Molecular docking of silibinin, oleanolic acid, and ursolic acid against the A26 protein (PDB ID: 6A9S). Left Panel: Visualization of the binding position of the ligand within the protein cavity. Central Panel: Ribbon diagram showing the docked complex. Ligands are shown in red. Right Panel: 2D diagram representing the interactions between phytochemicals and A26 protein generated by LigPlot. Dashed lines depict hydrogen bonds and the red arcs represent hydrophobic interactions. Rifampicin has been used as a control. Docking was performed via AutoDock Vina (Version 1.5.7) and the 3D structures were visualized using PyMol tool.
Figure 5
Figure 5
Molecular docking of silibinin, oleanolic acid, and ursolic acid against the H3 protein (PDB ID: 5EJ0). Left Panel: Visualization of the binding position of the ligand within the protein cavity. Central Panel: Ribbon diagram showing the docked complex. Ligands are shown in red. Right Panel: 2D diagram representing the interactions between phytochemicals and H3 protein generated by LigPlot. Dashed lines illustrate hydrogen bonding and the red arcs represent hydrophobic interactions. Rifampicin has been used as a control. Docking was performed via AutoDock Vina (Version 1.5.7) and the 3D structures were visualized using PyMol tool.
Figure 6
Figure 6
RMSD profile of protein backbone bound to phytomolecules in case of (A) A26 protein (B) H3 protein and (C) D13 protein.
Figure 7
Figure 7
RMSD profile of phytomolecules bound to (A) A26 protein (B) H3 protein and (C) D13 protein.
Figure 8
Figure 8
Radius of gyration (Rg) for the proteins bound to phytomolecules (A) A26 protein, (B) H3 envelop protein, and (C) D13 protein.
Figure 9
Figure 9
RMSF profile of (A) A26 protein and (B) H3 protein.
Figure 10
Figure 10
RMSF profile of the three monomers of the D13 protein respresented as (A–C).
Figure 11
Figure 11
Free energy contribution of (A) H3 residues, (B) A26 residues, (C) D13 residues (monomer-1), and (D) D13 residues (monomer-2) interacting with the three selected phytomolecules. Major residues with negative free energy contribution are highlighted.
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