Binary-QSAR guided virtual screening of FDA approved drugs and compounds in clinical investigation against SARS-CoV-2 main protease

Abstract

With the emergence of the new SARS-CoV-2 virus, drug repurposing studies have gained substantial importance. Combined with the efficacy of recent improvements in ligand- and target-based virtual screening approaches, virtual screening has become faster and more productive than ever. In the current study, an FDA library of approved drugs and compounds under clinical investigation were screened for their antiviral activity using the antiviral therapeutic activity binary QSAR model of the MetaCore/MetaDrug platform. Among 6733-compound collection, we found 370 compounds with a normalized therapeutic activity value greater than a cutoff of 0.75. Only these selected compounds were used for molecular docking studies against the SARS-CoV-2 main protease (M^pro). After initial short (10 ns) molecular dynamics (MD) simulations with the top-50 docking scored compounds and following molecular mechanics generalized born surface area (MM/GBSA) calculations, top-10 compounds were subjected to longer (100 ns) MD simulations and end-point MM/GBSA estimations. Our virtual screening protocol yielded Cefuroxime pivoxetil, an ester prodrug of second-generation cephalosporin antibiotic Cefuroxime, as being a considerable molecule for drug repurposing against the SARS-CoV-2 M^pro.

Keywords: SARS-CoV-2; drug repurposing; virtual screening; Binary QSAR.

Figure 1

Histogram of therapeutic activity predictions from the MetaCore/MetaDrug antiviral QSAR model for all 6733 compounds.

Figure 2

MM/GBSA score Box and Whisker plots for the selected top-10 compounds. MM/GBSA scores of 100 frames extracted from 100 ns simulations trajectories was considered.

Figure 3

(A) 3D representation of the Cefuroxime pivoxetil at binding site. The average frame from 100 ns trajectory was used. (B) 2D interaction diagram of Cefuroxime pivoxetil at Mpro binding site with residues around 3 Angstrom. (C) Time-dependent protein-ligand contact panel throughout 100 ns simulation. Top-panel shows total contacts, while bottom-panel shows formed/broken interaction between the protein and ligand.