In Silico Study towards Repositioning of FDA-Approved Drug Candidates for Anticoronaviral Therapy: Molecular Docking, Molecular Dynamics and Binding Free Energy Calculations

Abstract

The SARS-CoV-2 targets were evaluated for a set of FDA-approved drugs using a combination of drug repositioning and rigorous computational modeling methodologies such as molecular docking and molecular dynamics (MD) simulations followed by binding free energy calculations. Six FDA-approved drugs including, Ouabain, Digitoxin, Digoxin, Proscillaridin, Salinomycin and Niclosamide with promising anti-SARS-CoV-2 activity were screened in silico against four SARS-CoV-2 proteins-papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), SARS-CoV-2 main protease (Mpro), and adaptor-associated kinase 1 (AAK1)-in an attempt to define their promising targets. The applied computational techniques suggest that all the tested drugs exhibited excellent binding patterns with higher scores and stable complexes compared to the native protein cocrystallized inhibitors. Ouabain was suggested to act as a dual inhibitor for both PLpro and Mpro enzymes, while Digitoxin bonded perfectly to RdRp. In addition, Salinomycin targeted PLpro. Particularly, Niclosamide was found to target AAK1 with greater affinity compared to the reference drug. Our study provides comprehensive molecular-level insights for identifying or designing novel anti-COVID-19 drugs.

Keywords: anti-COVID-19; binding free energy; drug repositioning; molecular docking; molecular dynamic simulations.

Scheme 1

FDA-approved drugs that were included in the virtual study.

Figure 1

3D model of the interactions between cocrystallized ligand GRM (A), OUB (B), and SLM (C) with PLpro active site residues.

Figure 2

(A) RMSD and (B) RMSF plots for PLpro–GRM (red line), PLpro–OUB (blue line), and PLpro–SLM (black line). All values are reported in Å.

Figure 3

3D model of the interactions of cocrystallized ligand X77 (A) and OUB (B) with Mpro active site residues.

Figure 4

(A) RMSD and (B) RMSF plots for Mpro–X77 (red line) and Mpro–OUB (blue line). All values are reported in Å.

Figure 5

3D interactions between RDV (A) and DIG (B) with 7BV2 active site residues.

Figure 6

(A) RMSD and (B) RMSF plots for RdRp–RDV (red line) and RdRp–DIG (blue line). All values are reported in Å.

Figure 7

3D model of the interactions between crystallized ligand LKB (A) and NIS (B) in 5L4Q active site residues.

Figure 8

(A) RMSD and (B) RMSF plots for AAK1–LKB (red line) and AAK1–NIS (blue line). All values are reported in Å.

Figure 9

Residual decomposition plot for (A) PLpro (GRM, red; OUB, blue; SLM, black), (B) Mpro (X77, red; OUB, blue), (C) AAK1 (LKB, red; NIS, blue) and (D) RdRp (RDV, red; DIG, blue) systems. All values are reported in Kcal/mol.