Structural Homology-Based Drug Repurposing Approach for Targeting NSP12 SARS-CoV-2

Figures

• 

  Figure 1. Comparative analysis of the homologous structures identified using the DALI server. (A) Heatmap of correlational similarity among homologous structures based on Z-score. (B) Unrooted tree of the homologous protein structures clustered into four viral families; Coronaviridae, Caliciviridae, Flaviviridae, and Picornaviridae.

• 

  Figure 2. Analysis of the conserved motifs in NSP-12 and identification of druggable cavity. (A) Multiple sequences and secondary structure alignment of the homologous protein about NSP-12 of SARS-CoV-2 shows the conserved residues and secondary structure responsible for RdRp activity. Residues that have been highlighted in red are highly-conserved amino acids in the functional domain of RdRP protein. (B) Structurally and functionally conserved seven motifs A–G located at the active site of the RdRp domain of NSP-12. (C) The predicted druggable cavity at the active site of the RdRp domain of NSP-12. The predicted active residues participating in ligand interactions have been shown as a gray surface where the conserved residues are also located.

• 

  Figure 3. Comparison of conserved residues participating in ligand interactions and molecular docking score between NS5B and NSP-12. (A) A Venn diagram of active residues predicted from pharmacophore modeling and evolutionarily conserved residues of the RdRp domain of NSP-12. (B) Bar chart for comparison of binding energy score from AutoDock Vina between NSP-12 of SARS-CoV-2 and NS5B of HCV.

• 

  Figure 4. Receptor–ligand interaction profiling. The interactions between receptors, i.e., Nsp-12 and NS5B and ligands, i.e., Sofosbuvir and Dasabuvir. The dotted green line represents hydrogen bonding while the residues shown participate in hydrophobic interactions. (A) Interactions between NSP-12 and Sofosbuvir. (B) Interactions between NSP-12 and Dasabuvir. (C) Interactions between NS5B and Sofosbuvir. (D) Interactions between NS5B and Dasabuvir.

• 

  Figure 5. Structural stability analysis. RMSD of protein backbone vs. simulation time for solvated NSP-12 protein in complex with Dasabuvir, Ribavirin, and Sofosbuvir during 100 ns of molecular dynamics simulations.

• 

  Figure 6. Ligand-induced flexibility. Root mean square deviation (RMSF) values of NSP-12 alone and in a complex with Dasabuvir, Ribavirin, and Sofosbuvir vs. the number of residues.

• 

  Figure 7. Structural compactness of NSP-12. The radius of gyration (Rg) for backbone atoms of NSP-12 alone and in complex with Dasabuvir, Ribavirin, and Sofosbuvir throughout the simulation.

• 

  Figure 8. Intermolecular interactions. Hydrogen bonds numbers made between Dasabuvir, Ribavirin, and Sofosbuvir, with the NSP-12 protein active site residues during MD simulation.

• 

  Figure 9. The system’s temperature during 100 ns of MD simulation.