Computational investigations of potential inhibitors of monkeypox virus envelope protein E8 through molecular docking and molecular dynamics simulations

Abstract

The World Health Organization (WHO) has declared the monkeypox outbreak a public health emergency, as there is no specific therapeutics for monkeypox virus (MPXV) disease. This study focused on docking various commercial drugs and plant-derived compounds against the E8 envelope protein crucial for MPXV attachment and pathogenesis. The target protein structure was modeled based on the vaccinia virus D8L protein. Notably, maraviroc and punicalagin emerged as potential ligands, with punicalagin exhibiting higher binding affinity (- 9.1 kcal/mol) than maraviroc (- 7.8 kcal/mol). Validation through 100 ns molecular dynamics (MD) simulations demonstrated increased stability of the E8-punicalagin complex, with lower RMSD, RMSF, and Rg compared to maraviroc. Enhanced hydrogen bonding, lower solvent accessibility, and compact motions also attributed to higher binding affinity and stability of the complex. MM-PBSA calculations revealed van der Waals, electrostatic, and non-polar solvation as principal stabilizing energies. The binding energy decomposition per residue favored stable interactions between punicalagin and the protein's active site residues (Arg20, Phe56, Glu228, Tyr232) compared to maraviroc. Overall study suggests that punicalagin can act as a potent inhibitor against MPXV. Further research and experimental investigations are warranted to validate its efficacy and safety.

Keywords: E8; MPXV; Maraviroc; Molecular docking; Molecular dynamics simulations; Punicalagin.

Figure 1

A schematic representation of the workflow summarizing methodological steps.

Figure 2

A three-dimensional cartoon representation of the monkeypox virus envelope protein E8 (PDB entry: 4E9O_Chain A). The N- and C-terminal regions are shown in the figure.

Figure 3

Active binding pockets of MPXV E8 protein predicted from (A) PrankWeb and (B) CASTp.

Figure 4

Binding mode analysis of ligands with the protein’s active site residues during docking (A) MPXV E8-Maraviroc complex (i) A 2D plot (ii) stick model and (iii) surface representations of the docked conformer. (B) Structural representations of the docked MPXV E8-punicalagin complex in (i) 2D plot (ii) stick model and (iii) surface.

Figure 5

Protein–ligand interaction profile analysis using PLIP. (A). MPXV E8-Maraviroc interactions (B). The visual representation indicates hydrogen bonding interactions with a blue line, while hydrophobic interactions were illustrated in light grey. The ligand was depicted in a sphere form, with oxygen (O), nitrogen (N), and carbon (C) atoms represented by red, blue, and light orange colours, respectively.

Figure 6

Calculations of backbone RMS deviations for each trajectory of MPXV E8-Maraviroc and MPXV E8-punicalagin complexes from the initial position till 100 ns MD simulations. Colors: black, violet and cyan represent Traj1, Traj2 and Traj3 of MPXV E8-maraviroc complex; red, orange and green signify Traj1, Traj2 and Traj3 of MPXV E8-punicalagin complex.

Figure 7

RMS fluctuations of the MPXV E8 residues with maraviroc and punicalagin corresponding to 100 ns MD simulations. (a). Higher fluctuations of residues in MPXV E8-maraviroc complex (black), and lesser residue fluctuations observed over the length of the protein in the punicalagin-bound state (red). (b) is the location of the peak residues in the MPXV E8 protein bound with maraviroc (black) and punicalagin (red) respectively.

Figure 8

The radius of gyration measuring compactness of the envelope protein during 100 ns MD simulations. Higher gyrations were observed from the initial conformations till the end of the simulations in the MPXV E8-maraviroc complex (black). The MPXV E8-punicalagin complex maintains more compact and stable conformations by decreasing gyrations over time (Red).

Figure 9

Intermolecular H-bonding interactions of the protein–ligand complexes corresponding to 100 ns MD simulations. Lesser number of H-bonds in MPXV E8-maraviroc complex binding (Black). A higher number of H-bonds stabilize the MPXV E8-punicalagin complex (red). H-bonding pairs within 0.35 nm.

Figure 10

Binding pose analysis of protein–ligand complexes corresponding to 100 ns MD simulations (A). Structural changes in the MPXV E8-Maraviroc complex at 0 ns, 20 ns, 40 ns, 60 ns, 80 ns and 100 ns (B). Conformational transition upon punicalagin binding at 0 ns, 20 ns, 40 ns, 60 ns, 80 ns and 100 ns.

Figure 11

Interaction profile analysis of protein–ligand complexes at initial and end position of the simulations (A,B) Interactions of maraviroc with MPXV E8 at 0 and 100 ns (C,D) Interaction of punicalagin with MPXV E8 at 0 and 100 ns respectively.

Figure 12

SASA plot analysis corresponding to 100 ns MD simulations of MPXV E8-maraviroc and MPXV E8-punicalagin complex trajectory. Higher accessibility of MPXV E8 when treated with maraviroc (black). The accessibility decreases over a time scale of the simulation in the MPXV E8-punicalagin complex (red).

Figure 13

2D projections of the first two principal eigenvectors (PC1 and PC2) of MPXV E8-Maraviroc (black) and MPXV E8-Punicalagin (red) at 300 K corresponding to 100 ns MD simulations.

Figure 14

The binding free energy decomposition per residue of the protein–ligand complexes during 100 ns MD simulations. Residues with the lowest binding free energy profiles are highlighted.