Anti-HCV, nucleotide inhibitors, repurposing against COVID-19

Abstract

Aims: A newly emerged Human Coronavirus (HCoV) is reported two months ago in Wuhan, China (COVID-19). Until today >2700 deaths from the 80,000 confirmed cases reported mainly in China and 40 other countries. Human to human transmission is confirmed for COVID-19 by China a month ago. Based on the World Health Organization (WHO) reports, SARS HCoV is responsible for >8000 cases with confirmed 774 deaths. Additionally, MERS HCoV is responsible for 858 deaths out of about 2500 reported cases. The current study aims to test anti-HCV drugs against COVID-19 RNA dependent RNA polymerase (RdRp).

Materials and methods: In this study, sequence analysis, modeling, and docking are used to build a model for Wuhan COVID-19 RdRp. Additionally, the newly emerged Wuhan HCoV RdRp model is targeted by anti-polymerase drugs, including the approved drugs Sofosbuvir and Ribavirin.

Key findings: The results suggest the effectiveness of Sofosbuvir, IDX-184, Ribavirin, and Remidisvir as potent drugs against the newly emerged HCoV disease.

Significance: The present study presents a perfect model for COVID-19 RdRp enabling its testing in silico against anti-polymerase drugs. Besides, the study presents some drugs that previously proved its efficiency against the newly emerged viral infection.

Keywords: COVID-19; Docking; Nucleotide inhibitors; RdRp; Sofosbuvir; Structural bioinformatics; Wuhan coronavirus.

Fig. 1

(A) Multiple sequence alignment of all the HCoV strains (229E, NL63, HKU1, OC43, MERS, SARS, and COVID-19) RdRp sequences. Red highlights indicate identical residues while yellow highlighted residues are less conserved. Secondary structures are represented 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 while white is buried). The black dashed rectangles mark active site aspartates while blue rectangles mark the residues lying in the 5 Å region surrounding the active aspartates. The alignment is made using the Clustal omega web server and represented by ESpript 3. (B) The newly emerged COVID-19 RdRp model built by Swiss Model in the green cartoon (right) and surface (left) representations. Two views of the polymerase at 180^o rotation on the horizontal plane are shown (top and bottom). The active site aspartates are represented in red sticks for clarification (see the enlarged panel). (C) Ramachandran plot for the COVID-19 RdRp model. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 1

(A) Multiple sequence alignment of all the HCoV strains (229E, NL63, HKU1, OC43, MERS, SARS, and COVID-19) RdRp sequences. Red highlights indicate identical residues while yellow highlighted residues are less conserved. Secondary structures are represented 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 while white is buried). The black dashed rectangles mark active site aspartates while blue rectangles mark the residues lying in the 5 Å region surrounding the active aspartates. The alignment is made using the Clustal omega web server and represented by ESpript 3. (B) The newly emerged COVID-19 RdRp model built by Swiss Model in the green cartoon (right) and surface (left) representations. Two views of the polymerase at 180^o rotation on the horizontal plane are shown (top and bottom). The active site aspartates are represented in red sticks for clarification (see the enlarged panel). (C) Ramachandran plot for the COVID-19 RdRp model. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Binding energies calculated by AutoDock Vina for GTP, UTP, IDX-184, Sofosbuvir, Ribavirin, Remdisivir, Cinnamaldehyde, and Thymoquinone against COVID-19 (blue) and SARS HCoV (orange) RdRps. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

(A) The interactions that established after docking the DAA drugs IDX-184, Sofosbuvir, and Ribavirin against COVID-19 RdRp are presented. DAAs are in orange while the protein active site pocket in cyan sticks. H-bonds in solid blue lines while hydrophobic interactions are in dashed lines. Salt bridges are in yellow spheres connected by dashed lines. Its one-letter code labels RdRp residues, and the docking scores are listed under each complex. (B) The overall 3D structure complexes arranged as (A). Protein is represented in ribbon, and ligands are in sticks while the interacting residues of the RdRp are represented in colored lines. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)