Molecular Docking and In-Silico Analysis of Natural Biomolecules against Dengue, Ebola, Zika, SARS-CoV-2 Variants of Concern and Monkeypox Virus

Abstract

The emergence and rapid evolution of human pathogenic viruses, combined with the difficulties in developing effective vaccines, underline the need to develop innovative broad-spectrum antiviral therapeutic agents. The present study aims to determine the in silico antiviral potential of six bacterial antimicrobial peptides (AMPs), two phytochemicals (silvestrol, andrographolide), and two bacterial secondary metabolites (lyngbyabellin A, hapalindole H) against dengue virus, Zika virus, Ebola virus, the major variants of SARS-CoV-2 and monkeypox virus. The comparison of docking scores obtained with natural biomolecules was performed with specific neutralizing antibodies (positive controls for ClusPro) and antiviral drugs (negative controls for Autodock Vina). Glycocin F was the only natural biomolecule tested to show high binding energies to all viral surface proteins and the corresponding viral cell receptors. Lactococcin G and plantaricin ASM1 also achieved high docking scores with all viral surface proteins and most corresponding cell surface receptors. Silvestrol, andrographolide, hapalindole H, and lyngbyabellin A showed variable docking scores depending on the viral surface proteins and cell receptors tested. Three glycocin F mutants with amino acid modifications showed an increase in their docking energy to the spike proteins of SARS-CoV-2 B.1.617.2 Indian variant, and of the SARS-CoV-2 P.1 Japan/Brazil variant, and the dengue DENV envelope protein. All mutant AMPs indicated a frequent occurrence of valine and proline amino acid rotamers. AMPs and glycocin F in particular are the most promising biomolecules for the development of broad-spectrum antiviral treatments targeting the attachment and entry of viruses into their target cell.

Keywords: Ebola; SARS-CoV-2; Zika; bacterial AMPs; biomolecules; dengue; molecular docking; monkeypox.

Figure 1

The 3D visualization of the molecular docking of bacterial AMPs with viral surface proteins and their corresponding amino acid residues (highest binding affinities between AMPs and each viral protein were selected). The viral protein (receptor) is illustrated in purple and the bacterial AMP (ligand) is illustrated in blue.

Figure 2

Results of the docking analysis showing the 6 main binding sites of silvestrol with the different viral surface proteins. The molecular interactions in the 3D structures were visualized in PyMOL. (a) Indicates binding domain. (b) Binding site. (c) Interacting amino acids of receptor (purple) and ligand (blue).

Figure 3

Results of the docking analysis showing the 6main binding sites of andrographolide with the different viral surface proteins. The molecular interactions in the 3D structures were visualized in PyMOL. (a) Indicates binding domain. (b) Binding site. (c) Interacting amino acids of receptor (purple) and ligand (blue).

Figure 4

Results of the docking analysis showing the 6 main binding sites of lyngbyabellin A with the different viral surface proteins. The molecular interactions in the 3D structures were visualized in PyMOL. (a) Indicates binding domain. (b) Binding site. (c) Interacting amino acids of receptor (purple) and ligand (blue).

Figure 5

Results of the docking analysis showing the 6 main binding sites of hapalindole H with the different viral surface proteins. The molecular interactions in the 3D structures were visualized in PyMOL. (a) Indicates binding domain. (b) Binding site. (c) Interacting amino acids of receptor (purple) and ligand (blue).

Figure 6

Comparison of wild-type and mutant bacteriocin glycocin F. (a) Wild-type bacteriocin glycocin F against the spike (S) protein of SARS-CoV-2 B.1.617.2 Indian variant. (b) Mutant bacteriocin glycocin F against the spike (S) protein of SARS-CoV-2 B.1.617.2 Indian variant. (c) Wild-type bacteriocin glycocin F against the spike (S) protein of against SARS-CoV-2 P.1 Japan/Brazil variant. (d) Mutant bacteriocin glycocin F against the spike (S) protein of SARS-CoV-2 P.1 Japan/Brazil variant. Amino acid residues of the wild-type protein appear in purple, whereas rotamers of amino acid residues of mutant protein appear in gray.

Figure 7

Proposed antiviral mechanism of action of bacterial molecules and phytochemicals against DENV, EBOV, ZIKV, MPV, and SARS-CoV-2, by targeting the interaction between viral surface proteins and cell receptors (DC-SIGN, AXL, TIM-1, ACE2, Toll-like receptor 5, FcγRIIA, CR3/Mac-1 and CD36). Phytochemicals are incapable of binding with AXL and ACE2 cell receptors and lyngbyabellin A is unable to bind with the surface E protein of DENV. These natural biomolecules may contribute to reducing viral pathogenesis in host cells.