Remdesivir and Ledipasvir among the FDA-Approved Antiviral Drugs Have Potential to Inhibit SARS-CoV-2 Replication

Figures

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  Figure 1. Structure of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and its critical amino acid residues. On the right, a zoomed view of the active-site residues is shown in detail. RdRp is highlighted in green, and active-site binding residues are presented as cyan stick models.

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  Figure 2. Binding mode and hydrogen bonds of remdesivir, ledipasvir, and paritaprevir with RdRp. Detailed interactions occurring within 4 Å of the ligands are shown. RdRp is lime-green (transparent). Ligands ledipasvir, remdesivir, and paritaprevir are presented as orange stick models. (a) Interactions of remdesivir and the number of hydrogen bonds with important residues in the ligand-binding pocket of RdRp. (b) Binding mode of ledipasvir and the number of hydrogen bonds with RdRp. (c) Binding mode of paritaprevir and the number of hydrogen bonds with RdRp.

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  Figure 3. MD simulation results on apo-RdRp and complexes of RdRp with remdesivir, ledipasvir, and paritaprevir. (a) Root mean square deviation (RMSD) of the apo-form of RdRp and the complexes; (b) root mean square fluctuations (RMSFs) of the apo-form of RdRp and the complexes; (c) the radius of gyration (Rg) of the apo-form of RdRp and the complexes.

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  Figure 4. Projection of protein atoms in phase space along the first two principal eigenvectors. (a) The apo-RdRp protein; (b) the RdRp protein complexed with ledipasvir; (c) the RdRp protein complexed with remdesivir; (d) the RdRp protein complexed with paritaprevir.

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  Figure 5. The FEL of the first two principal components as a function of the radius of gyration (Rg) and root mean square deviation (RMSD). (a) The apo-RdRp protein; (b) the RdRp protein–remdesivir complex; (c) the RdRp protein–ledipasvir complex; and (d) the RdRp protein–paritaprevir complex. Snapshots were extracted from minimum energy wells.

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  Figure 6. The DCCMs. The DCCM for (a) the apo-RdRp form and for the RdRp complex with (b) remdesivir, (c) ledipasvir, (d) paritaprevir. The color gradients represent a positive (red) and negative (blue) correlation.

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  Figure 7. MM-PBSA binding free energy calculation. (a) Representative contributions of each energy component for RdRp with the selected drugs (remdesivir, ledipasvir, and paritaprevir). (b) The total binding free energy for RdRp in complex with the selected drugs.

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  Figure 8. In vitro evaluation of antiviral activity of the drug candidates against SARS-CoV-2. (a–c) The right vertical axis represents cell viability, and the left vertical axis denotes antiviral activity against SARS-CoV-2.