Biological and Medicinal Chemistry

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

Authors

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 MetaCoreTM/MetaDrugTM (https://portal.genego.com) platform's antiviral therapeutic activity binary QSAR model. In the 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 (Mpro). After initial short (10 ns) molecular dynamics (MD) simulations with the top-50 docked 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 pivotexil, an ester prodrug of second-generation cephalosporin antibiotic Cefuroxime, as being a considerable molecule for drug repurposing against the SARS-CoV-2 Mpro.

Content

Thumbnail image of MERGED-QSAR-paper2021.pdf