Molecular Investigation of SARS-CoV-2 Proteins and Their Interactions with Antiviral Drugs

Abstract

A new Coronavirus strain, named SARS-CoV-2, suddenly emerged in early December 2019. SARS-CoV-2 resulted in being dramatically infectious, with thousands of people infected. In this scenario, and without effective vaccines available, the importance of an immediate tool to support patients and against viral diffusion becomes evident. In this study, we exploit the molecular docking approach to analyze the affinity between different viral proteins and several inhibitors, originally developed for other viral infections. Our data show that, in some cases, a relevant binding can be detected. These findings support the hypothesis to develop new antiviral agents against COVID-19, on the basis of already established therapies.

Keywords: COVID-19; RNA-dependent RNA-polymerase; SARS–CoV-2; antiviral drug; coronavirus; molecular docking; molecular modeling; spike protein; viral protease; viral protein N.

Figure 1

Structural features of 3C-like protease from SARS–CoV-2. (a) Homology model structure with chain A shown as ribbons and chain B as molecular surface. Residues mutated with respect to the SARS–CoV homologue are shown as spheres. Active site residues are shown as stick. (b) Surface representation of the catalytic site of SARS–CoV Main protease (PDB ID: 5B6O) and of the crystallographic structure of inhibitor-bound SARS–CoV-2 3C-like protease (PDB ID: 6LU7). Hydrophobic residues are shown in cyan. Catalytic residues (His41, Cys145) are shown in green. Ala46Ser mutation is shown in orange on the SARS–CoV-2 structure.

Figure 2

Binding poses of the best scoring docked inhibitors. (a) Simeprevir; (b) Saquinavir; (c) Indinavir; (d) Tipranavir. Hydrophobic residues (Ala, Phe, Leu, Ile, Pro, Tyr, Val, Met, Trp, Gly) are colored in cyan. Catalytic residues are colored in green. N, O, C and S atoms are colored in blue, red, gray and yellow respectively.

Figure 3

Structural details of SARS–CoV-2 protease. (a) Ribbon representation of protease active site with side-chains of residues that interact with Simeprevir shown in full atom details. (b) Ribbon representation of the crystallographic structures of SARS–CoV-2 (blue, PDB ID: 6LU7) and HCV protease (light gray, PDB ID: 3KEE) superimposed. The hydrophobic loop Phe181–Phe185 of SARS-CoV-2 protease is evident on the upper side and is absent in HCV homologue. N, O, C and S atoms are colored in blue, red, gray and yellow respectively.

Figure 4

Structural representation of the spike trimer from SARS–CoV-2. (a) Molecular surface of the trimer structure, colored according to the local values of the electrostatic potential. The color palette ranges from −10 kcal/(mol·e) (red) to +10 kcal/(mol·e) (blue). (b) Top view of the same representation as in panel A. (c) Spike envelope protein from SARS-CoV. Same lateral view as in panel (a). (d) Top view of the same representation as in panel (c).

Figure 5

Best binding pose found with AutoDock Vina docking algorithm. (a) Enfuvirtide (shown in ribbon representation); (b) Umifenovir; (c) Pleconaril. The channel within the trimeric cap, is reported as a green circle. In panel (b) and (c), the transparent surface area indicates the localization of each inhibitor in the best five docking poses for Umifenovir (purple) and Pleconavir (green). The receptor-binding domains (RBD) are indicated by arrows in the middle panel as a reference.

Figure 6

Structural representation of the RdRp monomer from SARS–CoV-2. (a) Superposition with the structure poliovirus RdRp in complex with RNA primer (PDB id: 3OL6, only the nucleotide fragment is shown for clarity). The residues in contact with RNA primer are colored in red. (b) Same as in panel (a) but with SARS–CoV-2 RdRp molecular surface colored according to the electrostatic potential.

Figure 7

Structural representation of the homology model for Nucleocapsid monomer from SARS–CoV-2 shown in blue and superpose with the structure of the N-terminal fragment from IBV coronavirus homologue (colored in green, PDB ID: 2BXX) and with the dimerization domain of SARS RdRp (in red, PDB ID: 2GIB).