In Silico Screening and Molecular Dynamics Simulation Studies in the Identification of Natural Compound Inhibitors Targeting the Human Norovirus RdRp Protein to Fight Gastroenteritis

Abstract

Norovirus (HNoV) is a leading cause of gastroenteritis globally, and there are currently no treatment options or vaccines available to combat it. RNA-dependent RNA polymerase (RdRp), one of the viral proteins that direct viral replication, is a feasible target for therapeutic development. Despite the discovery of a small number of HNoV RdRp inhibitors, the majority of them have been found to possess a little effect on viral replication, owing to low cell penetrability and drug-likeness. Therefore, antiviral agents that target RdRp are in high demand. For this purpose, we used in silico screening of a library of 473 natural compounds targeting the RdRp active site. The top two compounds, ZINC66112069 and ZINC69481850, were chosen based on their binding energy (BE), physicochemical and drug-likeness properties, and molecular interactions. ZINC66112069 and ZINC69481850 interacted with key residues of RdRp with BEs of -9.7, and -9.4 kcal/mol, respectively, while the positive control had a BE of -9.0 kcal/mol with RdRp. In addition, hits interacted with key residues of RdRp and shared several residues with the PPNDS, the positive control. Furthermore, the docked complexes showed good stability during the molecular dynamic simulation of 100 ns. ZINC66112069 and ZINC69481850 could be proven as potential inhibitors of the HNoV RdRp in future antiviral medication development investigations.

Keywords: Norovirus; RdRp; gastroenteritis; natural compounds; viral replication.

Figure 1

Flow diagram of study design.

Figure 2

Visualization of ZINC66112069 in RdRp’s active site. 3D views of whole protein and ligand interactions (A), 3D views of interacting residues of the RdRp active site with ZINC66112069 (B), and 2D views of the RdRp residue interacting with ZINC66112069 (C).

Figure 3

Visualization of ZINC69481850 in RdRp’s active site. 3D views of whole protein and ligand interactions (A), 3D views of interacting residues of the RdRp active site with ZINC69481850 (B), and 2D views of the RdRp residue interacting with ZINC69481850 (C).

Figure 4

Visualization of PPNDS in RdRp’s active site. 3D views of whole protein and ligand interactions (A), 3D views of interacting residues of the RdRp active site with PPNDS (B), and 2D views of the RdRp residue interacting with PPNDS (C).

Figure 5

Complex structural stability studies. Protein backbone RMSD (A), Ligand RMSD plot (B), and RMSF of proteins (C). Control, ZINC69481850, and ZINC66112069 were shown in blue, red, and orange colors, respectively.

Figure 6

Radius of gyration of complexes (A), Number of H-Bonds in complexes (B), SASA plot (C), and Number of H-Bonds between RdRp and water molecules (D). PPNDS, ZINC69481850, and ZINC66112069 were shown in blue, red, and orange colors, respectively.