Structure Based Drug Repurposing Through Targeting Nsp9 Replicase and Spike Proteins of SARS-CoV-2
Due to unavailability of therapeutic approach for the novel coronavirus disease (COVID-19), the drug repurposing approach would be the fastest and efficient way of drug development against this deadly disease. We have applied bioinformatics approach for structure-based drug repurposing to identify the potential inhibitors through drug screening, molecular docking and molecular dynamics against non-structural protein 9 (Nsp9) replicase and spike proteins of the SARS-CoV-2 from the FDA approved drugs. We have performed virtual screening of 2000 FDA approved compounds including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis and active phytochemicals against Nsp9 replicase and spike proteins of SARS-CoV-2. Molecular docking was performed using Autodock-Vina. Selected hit compounds were identified based on their highest binding energy and favourable ADME profile. Notably, Conivaptan, an arginine vasopressin antagonist drug exhibited highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present on the active site of Nsp9 replicase. Additionally, Tegobuvir, a non-nucleoside inhibitor of hepatitis C virus exhibited maximum stability with highest binding energy (-8.1 Kcal/mol) on the active site of spike protein. Molecular docking scores were further validated with the molecular dynamics using Schrodinger, which supported strong stability of ligands with proteins at their active site through water bridges, hydrophobic interactions, H-bond. Overall, our findings highlight the fact that Conivaptan and Tegobuvir could be used to control the infection and propagation of SARS-CoV-2 targeting Nsp9 replicase and spike protein, respectively. Moreover, in vitro and in vivo validation of these findings will be helpful in bringing these molecules at the clinical settings.