Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (m^pro): a molecular docking, molecular dynamics and structure-activity relationship studies

Abstract

SARS-COV-2, the novel coronavirus and root of global pandemic COVID-19 caused a severe health threat throughout the world. Lack of specific treatments raised an effort to find potential inhibitors for the viral proteins. The recently invented crystal structure of SARS-CoV-2 main protease (M^pro) and its key role in viral replication; non-resemblance to any human protease makes it a perfect target for inhibitor research. This article reports a computer-aided drug design (CADD) approach for the screening of 118 compounds with 16 distinct heterocyclic moieties in comparison with 5 natural products and 7 repurposed drugs. Molecular docking analysis against M^pro protein were performed finding isatin linked with a oxidiazoles (<b>A2 and A4</b>) derivatives to have the best docking scores of -11.22 kcal/mol and -11.15 kcal/mol respectively. Structure-activity relationship studies showed a good comparison with a known active M^pro inhibitor and repurposed drug ebselen with an IC₅₀ value of -0.67 μM. Molecular Dynamics (MD) simulations for 50 ns were performed for <b>A2</b> and <b>A4</b> supporting the stability of the two compounds within the binding pocket, largely at the S1, S2 and S4 domains with high binding energy suggesting their suitability as potential inhibitors of M^pro for SARS-CoV-2.