Novel guanosine derivatives against MERS CoV polymerase: An in silico perspective

Abstract

The Middle East Respiratory Syndrome Coronavirus (MERS CoV), also termed camel flu, is a new viral infection that first reported in the year 2012 in the Middle East region and further spread during the last seven years. MERS CoV is characterized by its high mortality rate among different human coronaviruses. MERS CoV polymerase shares more than 20% sequence identity with the Hepatitis C Virus (HCV) Non-structural 5b (NS5b) RNA dependent RNA polymerase (RdRp). Despite the low sequence identity, the active site is conserved between the two proteins, with two consecutive aspartates that are crucial in the nucleotide transfer reaction. In this study, seven nucleotide inhibitors have been tested against MERS CoV RdRp using molecular modeling and docking simulations, from which four are novel compounds. Molecular Dynamics Simulation for 260 nanoseconds is performed on the MERS CoV RdRp model to test the effect of protein dynamics on the binding affinities to the tested nucleotide inhibitors. Results support the hypothesis of using the anti-polymerases (Anti-HCV drugs) against MERS CoV RdRp as a potent candidates. Besides four novel compounds are suggested as a seed for high performance inhibitors against MERS CoV RdRp.Communicated by Ramaswamy H. Sarma.

Keywords: HCV NS5b RdRp; MERS CoV; molecular docking; molecular dynamics simulation; polymerase.

Figure 1.

(A) Multiple sequence alignment of HCV RdRp and the different human coronaviruses RdRps. The secondary structure of HCV (from the PDB ID 2XI3) is presented above the sequence alignment. (B) Structural alignment between HCV RdRp (PDB ID 2XI3) (cyan) and MERS CoV RdRp model (brown) built, in silico, using I-TASSER web server. The enlarged panel shows the conservation of the active aspartates (D255 and D256 in MERS CoV (red) & D318 and D319 in HCV RdRps (green). The alignment was performed utilizing Maestro software from the Schrödinger package.

Figure 2.

(A) Backbone RMSD (blue line), RoG (orange line), Number of H-bonds (yellow line), and SASA (gray line) versus time (in nanoseconds) during the production MDS run on MERS CoV RdRp model. (B) Frequency distribution for the values of RMSD (blue), RoG (orange), number of H-bonds (yellow), and SASA (gray) during the 260 ns MDS run. (C) per-residue RMSF (green bars). The structure of the MERS CoV RdRp is represented in a green cartoon (right) and surface representation (left). Highly fluctuating regions are colored red and encircled in cyan. Arrows show each region in the RMSF bar graph. The active site aspartates are shown in magenta. (D) Binding energies versus time calculated with AutoDock Vina for the docking of different ligands to the active site of MERS CoV RdRp. The coordinates of the protein are extracted from the MDS at ten ns time intervals. Ligands are represented by different colors as shown in the chart legend.

Figure 3.

(A) 2D structures of the novel guanosine derivatives. (B) Average binding energies (kcal/mol) calculated for each ligand (from Figure 2B). UTP and GTP (blue) are used as positive controls. The four suggested compounds (green) are compared to the anti-HCV drugs (red).

Figure 4.

The binding modes for GTP and the four suggested compounds calculated by AutoDock Vina using the coordinates of MERS CoV RdRp at 64 ns of the MDS.