Exploration of Microbially Derived Natural Compounds against Monkeypox Virus as Viral Core Cysteine Proteinase Inhibitors

Abstract

Monkeypox virus (MPXV) is a member of the Orthopoxvirus genus and the Poxviridae family, which instigated a rising epidemic called monkeypox disease. Proteinases are majorly engaged in viral propagation by catalyzing the cleavage of precursor polyproteins. Therefore, proteinase is essential for monkeypox and a critical drug target. In this study, high-throughput virtual screening (HTVS) and molecular dynamics simulation were applied to detect the potential natural compounds against the proteinase of the monkeypox virus. Here, 32,552 natural products were screened, and the top five compounds were selected after implementing the HTVS and molecular docking protocols in series. Gallicynoic Acid F showed the minimum binding score of -10.56 kcal/mole in the extra precision scoring method, which reflected the highest binding with the protein. The top five compounds showed binding scores ≤-8.98 kcal/mole. These compound complexes were tested under 100 ns molecular dynamics simulation, and Vaccinol M showed the most stable and consistent RMSD trend in the range of 2 Å to 3 Å. Later, MM/GBSA binding free energy and principal component analysis were performed on the top five compounds to validate the stability of selected compound complexes. Moreover, the ligands Gallicynoic Acid F and H2-Erythro-Neopterin showed the lowest binding free energies of -61.42 kcal/mol and -61.09 kcal/mol, respectively. Compared to the native ligand TTP-6171 (ΔG_Bind = -53.86 kcal/mol), these two compounds showed preferable binding free energy, suggesting inhibitory application against MPXV proteinase. This study proposed natural molecules as a therapeutic solution to control monkeypox disease.

Keywords: antivirals; molecular dynamics; monkeypox virus; natural products; virtual screening.

Figure 1

Phases of compound screening along with compound (ligands) preparation using Schrödinger Release 2021–3 packages.

Figure 2

2D representation of the selected top five hit compounds derived after series of screening methods implemented on natural compounds against MPXV proteinase. * Name of the compound is not available.

Figure 3

3D and 2D interaction profile of the MPXV cysteine protease with the top screened natural compounds (a,b) Gallicynoic Acid F, (c,d) H2 Erythro-Neopterin, (e,f) Nigcollin C, (g,h) NPA024545, and (i,j) Vaccinol M.

Figure 4

3D position of initial and final docked poses of (a) Gallicynoic Acid F, (b) H2 Erythro-Neopterin, (c) Nigcollin C, (d) NPA024545, and (e) Vaccinol M extracted from the 100 ns MD simulation.

Figure 5

RMSD analysis on the docked viral proteins and ligands, i.e., natural compound trajectories (a) Gallicynoic Acid F, (b) H2 Erythro-Neopterin, (c) Nigcollin C, (d) NPA024545, and (e) Vaccinol M.

Figure 6

Protein–ligand interactions mapping for viral protein with selected natural compounds over the 100 ns simulation. (a) Gallicynoic Acid F, (b) H2 Erythro-Neopterin, (c) Nigcollin C, (d) NPA024545, and (e) Vaccinol M.

Figure 7

2D interaction diagram of protein–ligand contact for viral protein with selected natural compounds, i.e., (a) Gallicynoic Acid F, (b) H2 Erythro-Neopterin, (c) Nigcollin C, (d) NPA024545, and (e) Vaccinol M.

Figure 8

Principal component analysis of top five compounds. (a1–a4) Gallicynoic Acid F, (b1–b4) H2-Erythro-Neopterin, (c1–c4) Nigcollin C, (d1–d4) NPA024545, and (e1–e4) Vaccinol.