Analysis of SARS-CoV-2 RNA-dependent RNA polymerase as a potential therapeutic drug target using a computational approach

Abstract

Background: The Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) outbreak originating in Wuhan, China, has raised global health concerns and the pandemic has now been reported on all inhabited continents. Hitherto, no antiviral drug is available to combat this viral outbreak.

Methods: Keeping in mind the urgency of the situation, the current study was designed to devise new strategies for drug discovery and/or repositioning against SARS-CoV-2. In the current study, RNA-dependent RNA polymerase (RdRp), which regulates viral replication, is proposed as a potential therapeutic target to inhibit viral infection.

Results: Evolutionary studies of whole-genome sequences of SARS-CoV-2 represent high similarity (> 90%) with other SARS viruses. Targeting the RdRp active sites, ASP760 and ASP761, by antiviral drugs could be a potential therapeutic option for inhibition of coronavirus RdRp, and thus viral replication. Target-based virtual screening and molecular docking results show that the antiviral Galidesivir and its structurally similar compounds have shown promise against SARS-CoV-2.

Conclusions: The anti-polymerase drugs predicted here-CID123624208 and CID11687749-may be considered for in vitro and in vivo clinical trials.

Keywords: Active site; Homology modeling; Molecular Docking; Phylogenetic tree; RdRp; SARS-CoV-2.

Fig. 1

Dendrogram representing the phylogeny of viruses with SARS-CoV-2. Phylogenetic tree is divided into three clades, and all clades are further divided into sub-groups. 2019-SARS-CoV-2 from clade III is closely related to its relatives from Hong Kong and USA (circled in blue). For accessions, origin and other relevant data, see Additional file 1

Fig. 2

RdRp Sequence alignment of SARS-CoV and SARS-CoV-2. RdRp sequences of SARS-CoV and SARS-CoV-2 were aligned for analysis of divergence, the dark region represents the conserved regions and lighter regions highlight changes in amino acids in specific sites. Only 2.46% divergence was observed between the two RdRp protein sequences

Fig. 3

3D structure of SARS-CoV-2 RdRp using reference template (6NUR) predicted through PyMol9.19. The subdomains of RdRp are represented as follows: palm domain in green, thumb domain in blue, and finger domain in red

Fig. 4

Ramachandran plot for the model of RdRP SARS-CoV-2 protein representing 98% residues in most favored region, ~ 2% in allowed regions while 2% residues in outlier regions

Fig. 5

Dendrogram representing evolutionary relationship of RdRp proteins of SARS-CoV-2 with other RdRp proteins. SARS-CoV-2 accession (red circle) is closely associated with other SARS RdRp proteins (blue circle). For accessions, origin and other relevant data, see Additional file 1: Data 2

Fig. 6

Ligand interaction with conserved amino acid residues of RdRp. a RdRp-ligand (CID-11687749; red) inhibitor complex. b Ligand conformation in active site of RdRp; the pink dotted line represents H-bonding between the amino acid residues of RdRp and ligand. c 2D representation of ligand interaction with receptor (RdRp). H-bonding of residues ASP760, ASP761, GLU811, TRP800, and LYS798 of RdRp with inhibitor CID-11687749. a and b were analyzed with PyMol 9.1 while c was analyzed using MOE software

Fig. 7

Ligand interaction with conserved amino acid residues of RdRp. a RdRp-ligand (CID-123624208; green) inhibitor complex. b Ligand conformation in active site of RdRp; yellow dotted line represents H-bonding between the amino acid residues of RdRp and ligand CID-123624208; (green). c 2D representation ligand interaction with receptor (RdRp). H-bonding residues ASP760, ASP761, SER814, and LYS798 of RdRP with inhibitor (CID-123624208) are shown with the green line. a, b were analyzed with PyMol 9.1 while c was analyzed using MOE software

Fig. 8

2D structure of selected inhibitor with respective PubChem IDs

Fig. 9

Ligand interaction with conserved amino acid residues of RdRp. a RdRp-Galidesivir inhibitor complex, Galidesivir represented in blue color. b Shows the ligand interaction in active site of RdRp. Yellow doted lines represent the H-Bonding (hydrogen bonding) between the amino acid residues of RdRp and ligand Galidesivir (blue color). c 2D representation of ligand interaction with receptor (RdRp). H-bonding residues ASP-761, ALA-762, LYS-798, and SER-814 of RdRp with inhibitor Galidesivir are shown in green dotted line. a and b were analyzed by PyMol 9.1 while c was analyzed by MOE