Identification of SARS-CoV-2 Papain-like Protease (PLpro) Inhibitors Using Combined Computational Approach

Abstract

In the current pandemic, finding an effective drug to prevent or treat the infection is the highest priority. A rapid and safe approach to counteract COVID-19 is in silico drug repurposing. The SARS-CoV-2 PLpro promotes viral replication and modulates the host immune system, resulting in inhibition of the host antiviral innate immune response, and therefore is an attractive drug target. In this study, we used a combined in silico virtual screening for candidates for SARS-CoV-2 PLpro protease inhibitors. We used the Informational spectrum method applied for Small Molecules for searching the Drugbank database followed by molecular docking. After in silico screening of drug space, we identified 44 drugs as potential SARS-CoV-2 PLpro inhibitors that we propose for further experimental testing.

Keywords: ISM; Papain-like protease; SARS-CoV-2; drug repurposing; molecular docking.

Figure 1

ISM spectrum of SARS‐CoV‐2 Papain like protease.

Figure 2

Crystal structure of PLpro, with a marked catalytic triad (PDBID 6WUU). Marked regions correspond F(0.383) 248–312 – blue, and F(0.279) 60–124 – green. The bound compound is the co‐crystallized covalent peptide inhibitor VIR250.

Figure 3

Epicriptine in the PLpro inhibitor binding site, with marked interacting amino acid residues and corresponding distances. Green lines: hydrogen bonds; light green: N−H‐π interactions or carbon hydrogen bond; orange: electrostatic or anion‐π interactions; purple: alkyl‐π interactions. The distance of each interaction is presented in Å.

Figure 4

Metergoline in the PLPro inhibitor binding site. with marked interacting amino acid residues and corresponding distances. Green lines: hydrogen bonds; light green: N−H‐π interactions; orange: electrostatic interactions; purple: alkyl‐π interactions, magenta: π‐π interactions. The distance of each interaction is presented in Å.

Figure 5

Ergometrine in the PLpro inhibitor binding site, with marked interacting amino acid residues and corresponding distances. Green lines: hydrogen bonds; light green: N−H‐π interactions or carbon hydrogen bonds; orange: electrostatic interactions or anion‐π interactions; purple: alkyl‐π interactions, magenta: π‐π interactions. The distance of each interaction is given in Å.

Figure 6

Co crystalized ligand GRL 0617 in the PLpro allosteric site with marked interacting amino acid residues and corresponding distances. Green lines: hydrogen bonds; purple: alkyl‐π/hydrophobic interactions. The distance of each interaction is given in Å.

Figure 7

PMF during the metadynamics simulation of the Plpro‐metergoline complex. The Red line represents averaged multiple PMF curves in the range from 4.11 and 4.16 ns of the metadynamics simulation.