SARS-CoV-2 and SARS-CoV: Virtual screening of potential inhibitors targeting RNA-dependent RNA polymerase activity (NSP12)

Abstract

Since the outbreak of severe acute respiratory syndrome (SARS) in 2003, the harm caused by coronaviruses to the world cannot be underestimated. Recently, a novel coronavirus (severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2]) initially found to trigger human severe respiratory illness in Wuhan City of China in 2019, has infected more than six million people worldwide by 21 June 2020, and which has been recognized as a public health emergency of international concern as well. And the virus has spread to more than 200 countries around the world. However, the effective drug has not yet been officially licensed or approved to treat SARS-Cov-2 and SARS-Cov infection. NSP12-NSP7-NSP8 complex of SARS-CoV-2 or SARS-CoV, essential for viral replication and transcription, is generally regarded as a potential target to fight against the virus. According to the NSP12-NSP7-NSP8 complex (PDB ID: 7BW4) structure of SARS-CoV-2 and the NSP12-NSP7-NSP8 complex (PDB ID: 6NUR) structure of SARS-CoV, NSP12-NSP7 interface model, and NSP12-NSP8 interface model were established for virtual screening in the present study. Eight compounds (Nilotinib, Saquinavir, Tipranavir, Lonafarnib, Tegobuvir, Olysio, Filibuvir, and Cepharanthine) were selected for binding free energy calculations based on virtual screening and docking scores. All eight compounds can combine well with NSP12-NSP7-NSP8 in the crystal structure, providing drug candidates for the treatment and prevention of coronavirus disease 2019 and SARS.

Keywords: COVID-19; NSP12-NSP7-NSP8; SARS-CoV; SARS-CoV-2; antiviral drugs; drug candidates.

Figure 1

The docking boxes of the NSP12‐NSP7 interface and NSP12‐NSP8 interface. The yellow part is nsp12. The green part is nsp7. The cyan part is nsp8. The docking box on the left is NSP12‐NSP7 interface. The docking box on the right is NSP12‐NSP8 interface

Figure 2

The binding model of Nilotinib against SARS‐CoV‐2 NSP12‐NSP7. A, Interactions between Nilotinib (cyan) and associated residues (off‐white) in the interface of the homology model for SARS‐CoV‐2. B, Binding models of Nilotinib (cyan) in the SARS‐CoV‐2 NSP12‐NSP7 protein interface pocket (white surface). Numbers accompanying dashed yellow lines represent the interaction distance (Å). SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2

Figure 3

The binding model of Saquinavir and Tipranavir against SARS‐CoV NSP12‐NSP7. A, Interactions between Saquinavir (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV. B, Binding models of Saquinavir (cyan) in the SARS‐CoV NSP12‐NSP7 protein interface pocket (white surface). C, Interactions between Tipranavir (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV. D, Binding models of Tipranavir (cyan) in the SARS‐CoV NSP12‐NSP7 protein interface pocket (white surface). Numbers accompanying dashed yellow lines represent the interaction distance (Å). SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2

Figure 4

The binding model of Lonafarnib against SARS‐CoV‐2 and SARS‐CoV NSP12‐NSP7. A, Interactions between Lonafarnib (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV‐2. B, Binding models of Lonafarnib (cyan) in the SARS‐CoV‐2 NSP12‐NSP7 protein interface pocket (white surface). C, Interactions between Lonafarnib (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV. D, Binding models of Lonafarnib (cyan) in the SARS‐CoV NSP12‐NSP7 protein interface pocket (white surface). SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2

Figure 5

The binding model of Tegobuvir against SARS‐CoV‐2 and SARS‐CoV. A, Interactions between Tegobuvir (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV‐2. B, Binding models of Tegobuvir (cyan) in the SARS‐CoV‐2 NSP12‐NSP7 protein interface pocket (white surface). C, Interactions between Tegobuvir (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV‐2. D, Binding models of Tegobuvir (cyan) in the SARS‐CoV‐2 NSP12‐NSP8 protein interface pocket (white surface). E, Interactions between Tegobuvir (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV. F, Binding models of Tegobuvir (cyan) in the SARS‐CoV NSP12‐NSP7 protein interface pocket (white surface). G, Interactions between Tegobuvir (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV. H, Binding models of Tegobuvir (cyan) in the SARS‐CoV NSP12‐NSP8 protein interface pocket (white surface). Numbers accompanying dashed yellow lines represent the interaction distance (Å, C). SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2

Figure 6

The binding model of Olysio against SARS‐CoV‐2 and SARS‐CoV NSP12‐NSP8. A, Interactions between Olysio (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV‐2. B, Binding models of Olysio (cyan) in the SARS‐CoV‐2 NSP12‐NSP8 protein interface pocket (white surface). C, Interactions between Olysio (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV‐2. D, Binding models of Olysio (cyan) in the SARS‐CoV‐2 NSP12‐NSP8 protein interface pocket (white surface). Numbers accompanying dashed yellow lines represent the interaction distance (Å, C). SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2

Figure 7

The binding model of Cepharanthine against SARS‐CoV‐2 and SARS‐CoV. A, Interactions between Cepharanthine (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV‐2. B, Binding models of Cepharanthine (cyan) in the SARS‐CoV‐2 NSP12‐NSP7 protein interface pocket (white surface). C, Interactions between Cepharanthine (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV‐2. D, Binding models of Cepharanthine (cyan) in the SARS‐CoV‐2 NSP12‐NSP8 protein interface pocket (white surface). E, Interactions between Cepharanthine (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV. F, Binding models of Cepharanthine (cyan) in the SARS‐CoV NSP12‐NSP8 protein interface pocket (white surface). SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2

Figure 8

The binding model of Filibuvir against SARS‐CoV‐2 and SARS‐CoV NSP12‐NSP8. A, Interactions between Filibuvir (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV‐2. B, Binding models of Filibuvir (cyan) in the SARS‐CoV‐2 NSP12‐NSP8 protein interface pocket (white surface). C, Interactions between Filibuvir (cyan) and associated residues (off‐white) in the interface of the crystal structure for SARS‐CoV. D, Binding models of Filibuvir (cyan) in the SARS‐CoV NSP12‐NSP8 protein interface pocket (white surface). Numbers accompanying dashed yellow lines represent the interaction distance (Å). SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2