Structure-based drug repurposing for targeting Nsp9 replicase and spike proteins of severe acute respiratory syndrome coronavirus 2

Abstract

Drug re-purposing might be a fast and efficient way of drug development against the novel coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We applied a bioinformatics approach using molecular dynamics and docking to identify FDA-approved drugs that can be re-purposed to potentially inhibit the non-structural protein 9 (Nsp9) replicase and spike proteins in SARS-CoV-2. We performed virtual screening of FDA-approved compounds, including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis, and active phytochemicals against the Nsp9 replicase and spike proteins. Selected hit compounds were identified based on their highest binding energy and favorable absorption, distribution, metabolism and excretion (ADME) profile. Conivaptan, an arginine vasopressin antagonist drug exhibited the highest binding energy (-8.4 Kcal/ mol) and maximum stability with the amino acid residues present at the active site of the Nsp9 replicase. Tegobuvir, a non-nucleoside inhibitor of the hepatitis C virus, also exhibited maximum stability along with the highest binding energy (-8.1 Kcal/mol) at the active site of the spike proteins. Molecular docking scores were further validated by molecular dynamics using Schrodinger, which supported the strong stability of ligands with the proteins at their active sites through water bridges, hydrophobic interactions, and H-bonding. Our findings suggest Conivaptan and Tegobuvir as potential therapeutic agents against SARS-CoV-2. Further in vitro and in vivo validation and evaluation are warranted to establish how these drug compounds target the Nsp9 replicase and spike proteins.

Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2

“…This screening confirms previous reports demonstrating anti-SARS-CoV-2 activity of hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, celecoxib, and thioridazine hydrochloride (8)(9)(10)(25)(26)(27), while identifying additional 12 drugs. However, there are seven drugs have been reported when our manuscript was underreview (28)(29)(30)(31)(32)(33)(34)(35)(36)(37). The underlying mechanisms of viral replication inhibition by these drugs are not clear.…”

Protease inhibitors targeting the main protease and papain-like protease of coronaviruses

“…Therefore, they are probably more druggable with respect to the other Nsps, which are completely protected inside the DMV. Nsp9, an ssRNA binding protein, is believed to mediate viral replication and virulence [35]. Nsp12 (Figure 1), known as RNA-dependent RNA polymerase (RdRp), which uses the viral RNA as a template to make a new copy of the viral RNA [34], and, finally, the Nsp13, a protein known as helicase, separates and/or rearranges nucleic acid duplexes in reactions fueled by adenosine triphosphate (ATP) hydrolysis [36].…”

Unpacking Pandora from Its Box: Deciphering the Molecular Basis of the SARS-CoV-2 Coronavirus

“…Such studies of the novel coronavirus Nsp9 will assist in drug screening strategies targeting the dimer interface with the view to compromising its replication ability. Recently, it has been reported that Conivaptan, Telmisartan, and Phaitanthrin D exhibited favorable docking scores against the target site of the Nsp9 replicase (PDB ID-6W4B) and suggests their potential usage as therapeutic agents against SARS-CoV-2 [ 51 ].…”

“…It is believed that the spike is responsible for the cellular internalization of SARS-CoV-2, host tissue tropism and coronavirus transmission capacity [ 75 ]. It has been suggested that the SARS-CoV-2 Spike differs by 12.8% from that of SARS-CoV [ 51 ]. While such variation in the spike protein amino acid composition exists, this study reported no overall difference in their structures.…”

“…While such variation in the spike protein amino acid composition exists, this study reported no overall difference in their structures. Of note however, was the discovery of various novel N- and O linked glycosylation sites (e.g., NGTK, NFTI, NLTT, and NTSN) in the spike of SARS-CoV-2 compared to SARS-CoV [ 51 , 76 ]. It has been proposed that such unique features contribute to the shielding and camouflage of SARS-CoV-2 from the defense system of the host [ 76 ].…”