The anti-HCV, Sofosbuvir, versus the anti-EBOV Remdesivir against SARS-CoV-2 RNA dependent RNA polymerase in silico

Abstract

Coronavirus diseases 2019 (COVID-19) are seriously affecting human health all over the world. Nucleotide inhibitors have promising results in terms of its efficacy against different viral polymerases. In this study, detailed molecular docking and dynamics simulations are used to evaluate the binding affinity of a clinically approved drug, sofosbuvir, with the solved structure of the viral protein RNA-dependent RNA polymerase (RdRp) and compare it to the clinically approved drug, Remdesivir. These drugs are docked onto the three-dimensional structure of the nsp12 protein of SARS-CoV-2, which controls the polymerization process. Hence, it is considered one of the primary therapeutic targets for coronaviruses. Sofosbuvir is a drug that is currently used for HCV treatment; therefore, HCV RdRp is used as a positive control protein target. The protein dynamics are simulated for 100 ns, while the binding is tested during different dynamics states of the SARS-CoV-2 RdRp. Additionally, the drug-protein complexes are further simulated for 20 ns to explore the binding mechanism. The interaction of SARS-CoV-2 RdRp as a target with the active form of sofosbuvir as a ligand demonstrates binding effectiveness. One of the FDA-approved antiviral drugs, such as sofosbuvir, can help us in this mission, aiming to limit the danger of COVID-19. Sofosbuvir was found to bind nsp12 with comparable binding energies to that of Remdesivir, which has been reported for its potential against COVID-19 RdRp and is currently approved by the FDA.

An Analysis of Inhibition of the Severe Acute Respiratory Syndrome Coronavirus 2 RNA-dependent Rna Polymerase By Zinc Ion: an in silico Approach

“…D760 and D761 are located in motif C, forming the conserved (Table 1) catalytic residues (759-SDD−761), analogous to 317-GDD−319 in HCV ns5b and 327-GDD−329 poliovirus' 3Dpol [20,[44][45][46]. These residues have also been linked to inhibition of RdRp by Remdesivir and Sofosbuvir [47,48].…”

Molecular dynamics simulations and MM-GBSA reveal novel guanosine derivatives against SARS-CoV-2 RNA dependent RNA polymerase

“…Guanosine triphosphate (GTP), sofosbuvir, ribavirin, and remdesivir were used as positive controls, while cinnamaldehyde and thymoquinone were selected as negative controls. 8,15 AutoDock Tools 1.5.6 was utilized to prepare ligands and the different protein conformations (merging Gasteiger charges and generating dockable PDBQT format for molecular docking). 43 The receptor grid boxes for the twenty conformations of SARS-CoV-2 RdRp were adjusted to cover the binding site represented by D760 and D761, which were treated as flexible during the docking simulations.…”

Targeting SARS-CoV-2 Nonstructural Protein 15 Endoribonuclease: an in silico Perspective

“…On the other hand, ribavirin is a synthetic guanosine nucleoside used for its broad-spectrum activity against several RNA and DNA viruses [18]. Remdesivir is a promising antiviral drug against various RNA viruses, including the Ebola virus, SARS-CoV and Middle East respiratory syndrome (MERS) coronavirus [19][20][21]. At the same time, it was recently approved by the FDA for the treatment of the Ebola virus and SARS-CoV-2 (emergency use only approval) [22,23].…”