Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study

Abstract

Aims: A new human coronavirus (HCoV), which has been designated SARS-CoV-2, began spreading in December 2019 in Wuhan City, China causing pneumonia called COVID-19. The spread of SARS-CoV-2 has been faster than any other coronaviruses that have succeeded in crossing the animal-human barrier. There is concern that this new virus will spread around the world as did the previous two HCoVs-Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)-each of which caused approximately 800 deaths in the years 2002 and 2012, respectively. Thus far, 11,268 deaths have been reported from the 258,842 confirmed infections in 168 countries.

Main methods: In this study, the RNA-dependent RNA polymerase (RdRp) of the newly emerged coronavirus is modeled, validated, and then targeted using different anti-polymerase drugs currently on the market that have been approved for use against various viruses.

Key findings: The results suggest the effectiveness of Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir as potent drugs against SARS-CoV-2 since they tightly bind to its RdRp. In addition, the results suggest guanosine derivative (IDX-184), Setrobuvir, and YAK as top seeds for antiviral treatments with high potential to fight the SARS-CoV-2 strain specifically.

Significance: The availability of FDA-approved anti-RdRp drugs can help treat patients and reduce the danger of the mysterious new viral infection COVID-19. The drugs mentioned above can tightly bind to the RdRp of the SARS-CoV-2 strain and thus may be used to treat the disease. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA.

Keywords: COVID-19; Drug repurposing; Molecular docking; RdRp; SARS-CoV-2; Structural bioinformatics.

Graphical abstract

Fig. 1

(A) Phylogenetic analysis of the RdRps of 7 HCoVs (229E, NL63, HKU1, OC43, MERS, SARS, and Wuhan SARS-CoV-2) (cladogram); (B) Multiple sequence alignment of the HCoV RdRp sequences utilizing the Clustal Omega web server and represented by ESpript. Red highlights indicate identical residues while yellow-highlighted residues are less conserved. Secondary structures are described at the top of the MSA for SARS RdRp (PDB ID: 6NUR, chain A), while the surface accessibility is shown at the bottom (blue: highly accessible; white: buried). Active site aspartates (D255 and D256) are marked on the MSA. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Bar graph representing the binding energies (in kcal/mol) calculated by AutoDock Vina software for GTP, UTP, CTP, ATP, Cinnamaldehyde, Thymoquinone, Galidesivir, Remdesivir, Tenofovir, Sofosbuvir, Ribavirin, Uprifosbuvir, Setrobuvir, Balaprevir, MK0608, R7128, IDX-184, 2′C-methylcytidine, BMS-986094, YAK, PSI-6130, PSI-6206, R1479, and Valopectibine against SARS-CoV-2 RdRp (blue), SARS HCoV RdRp (orange), and HCV NS5B RdRp (gray). The dashed-red rectangles mark the best three compounds. The dashed green box marks the five drugs (approved by FDA against HCV, EBOV, and HIV). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Interactions established after docking the (A) GTP, Ribavirin, Sofosbuvir, and Tenofovir and (B) IDX-184, Setrobuvir, and YAK against SARS-CoV-2 RdRp. Drugs are in orange, while cyan lines represent the active protein site pockets. Solid blue lines depict H-bonds, while hydrophobic interactions are gray dashed lines. Additionally, salt bridges, π-cation stacking, and halogen contacts are represented by yellow spheres connected by black dashed lines, orange dashed lines, and cyan lines, respectively. RdRp residues are labeled, and the docking scores are listed under each complex. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)