The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA polymerase

Abstract

An outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan and it has rapidly spread to almost all parts of the world. For coronaviruses, RNA-dependent RNA polymerase (RdRp) is an important polymerase that catalyzes the replication of RNA from RNA template and is an attractive therapeutic target. In this study, we screened these chemical structures from traditional Chinese medicinal compounds proven to show antiviral activity in severe acute respiratory syndrome coronavirus (SARS-CoV) and the similar chemical structures through a molecular docking study to target RdRp of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). We found that theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS-CoV-2 (-9.11 kcal/mol), SARS-CoV (-8.03 kcal/mol), and MERS-CoV (-8.26 kcal/mol) from idock. To confirm the result, we discovered that theaflavin has lower binding energy of -8.8 kcal/mol when it docks in the catalytic pocket of SARS-CoV-2 RdRp by using the Blind Docking server. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were found between theaflavin and RdRp. Moreover, one π-cation interaction was formed between theaflavin and Arg553 from the Blind Docking server. Our results suggest that theaflavin could be a potential SARS-CoV-2 RdRp inhibitor for further study.

Keywords: RNA-dependent RNA polymerase; SARS-CoV-2; theaflavin; traditional Chinese medicinal compounds.

Figure 1

(A) Sequence alignment for the amino acids of RdRp between SARS‐CoV‐2, SARS‐CoV, and MERS‐CoV. (B) A modeled structure of SARS‐CoV‐2 RdRp, SARS‐CoV RdRp, and MERS‐CoV RdRp and Grid box size for binding site using MODELLER. The active site (Val557) and grid box size (light yellow) were showed for binding site. MERS, Middle East respiratory syndrome; RdRp, RNA‐dependent RNA polymerase; SARS‐CoV, severe acute respiratory syndrome coronavirus

Figure 2

(A) The structure of theaflavin (ZINC3978446). (B) Red and green molecules, respectively, represent crystallographic and predicted pose for theaflavin. (C‐E) The contact model between theaflavin and SARS‐CoV‐2 RdRp (C), SARS‐CoV RdRp (D), and MERS‐CoV RdRp (E) are shown in two‐dimensional (2D) interaction diagram by idock. (F) The contact model between theaflavin and SARS‐CoV‐2 RdRp is shown in the 2D interaction diagram by the Blind Dock server. Their relative distances between amino acid residues and theaflavin are analyzed and illustrated by LigPlot+. Carbon, oxygen, nitrogen, and fluoride molecules are marked as white, red, blue, and green circles, respectively. Covalent bonds in theaflavin and amino acid residues of RdRp are labeled in purple and orange solid lines, respectively. The light blue dot lines label the distance (in Å) of hydrogen bonds formed between the functional moieties of theaflavin and amino acid residues. Hydrophobic interactions between theaflavin and RdRp are depicted by the name of involving amino acid residues, which are labeled with dark green with dark red eyelashes pointing to the involved functional moiety of theaflavin. (G) The hydrogen bonds and π‐cation interaction established by theaflavin with the closest residues are showed through Protein‐Ligand Interaction Profiler (PLIP). MERS, Middle East respiratory syndrome; RdRp, RNA‐dependent RNA polymerase; SARS‐CoV, severe acute respiratory syndrome coronavirus