Structure Based Drug Repurposing Through Targeting Nsp9 Replicase and Spike Proteins of SARS-CoV-2

Abstract

<p>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, <i>in vitro</i> and <i>in vivo</i> validation of these findings will be helpful in bringing these molecules at the clinical settings.</p>

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

“…Some examples of potential disruptors of the S glycoprotein interaction with ACE2, identi ed by simple molecular docking of approved drugs include hesperidin [72], paritaprevir [44], cladribine, clofarabine, and udarabine [14]. Differently, docking combined with MD simulations highlighted denopamine, bometolol, naminterol, rotigaptide, benzquercin [19], simeprevir, lumacaftor [63], tegobuvir, bromocriptine, baicalin [6], KT185, KT203, GSK1838705A, and BMS195614 [9] as potential binders of the RBD.…”

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

“…Some examples of potential disruptors of the S glycoprotein interaction with ACE2, identified by simple molecular docking of approved drugs include hesperidin [30], paritaprevir [31], cladribine, clofarabine, and fludarabine [32]. Differently, docking combined with MD simulations highlighted denopamine, bometolol, naminterol, rotigaptide, benzquercin [33], simeprevir, lumacaftor [34], tegobuvir, bromocriptine, baicalin [35], KT185, KT203, GSK1838705A, and BMS195614 [36] as potential binders of the RBD.…”