Computational drug repurposing study of the RNA binding domain of SARS‐CoV‐2 nucleocapsid protein with antiviral agents

Abstract

The recent outbreak of coronavirus disease (COVID‐19) in China caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has led to worldwide human infections and deaths. The nucleocapsid (N) protein of coronaviruses (CoVs) is a multifunctional RNA binding protein necessary for viral RNA replication and transcription. Therefore, it is a potential antiviral drug target, serving multiple critical functions during the viral life cycle. This study addresses the potential to repurpose antiviral compounds approved or in development for treating human CoV induced infections against SARS‐CoV‐2 N. For this purpose, we used the docking methodology to better understand the inhibitory mechanism of this protein with the existing 34 antiviral compounds. The results of this analysis indicate that rapamycin, saracatinib, camostat, trametinib, and nafamostat were the top hit compounds with binding energy (−11.87, −10.40, −9.85, −9.45, −9.35 kcal/mol, respectively). This analysis also showed that the most common residues that interact with the compounds are Phe66 , Arg68 , Gly69 , Tyr123 , Ile131 , Trp132 , Val133 , and Ala134 . Subsequently, protein‐ligand complex stability was examined with molecular dynamics simulations for these five compounds, which showed the best binding affinity. According to the results of this study, the interaction between these compounds and crucial residues of the target protein were maintained. These results suggest that these residues are potential drug targeting sites for the SARS‐CoV‐2 N protein. This study information will contribute to the development of novel compounds for further in vitro and in vivo studies of SARS‐CoV‐2, as well as possible new drug repurposing strategies to treat COVID‐19 disease.

Viewing SARS-CoV-2 Nucleocapsid Protein in Terms of Molecular Flexibility

“…In a recent study, combination of molecular docking and MD simulation was employed to identify potential antiviral drugs and investigate the stability of the NTD-drug complexes [ 31 ]. 34 antiviral compounds, which were already approved or in development, were focused on because such molecules do not need long-term preclinical studies and thus, they would be excellent candidates in the case of disease outbreaks.…”

“…Ivermectin, an anti-parasitic drug with antiviral properties, has also been shown to bind to the similar region as the above compounds [ 32 ]. Although each compound also interacts with the residues of the NTD other than those shown in Figure 3 a, none of these residues overlaps with the RNA-binding region except for rapamycin, which shares K65 with the RNA-binding sites [ 31 ]. It is likely that the binding affinity between the NTD and RNA is affected as long as at least one residue is blocked by a drug molecule.…”

“…After identifying the above compounds that bind to the NTD with high affinity, the stability of the NTD-drug complexes was investigated using MD simulation at 300 K for 25 ns [ 31 ]. It was found that the root-mean-square-fluctuation (RMSF), which reflects the magnitude of thermal motions of amino acid residues, of all the complexes is between 0.42 nm and 1.32 nm, suggesting that the complexes are highly stable.…”

“…The RNA-bounded form of the NTD is shown (PDB ID: 7ACT [ 13 ]). ( a ) Amino acid residues of N CoV2 NTD involved in the interaction with antiviral compounds that show high binding affinity are shown in orange (F66, R68, G69, Y123, I131, W132, V133 and A134 [ 31 ]). These residues commonly interact with the compounds.…”

Comparative Analysis of Small Moleclues and Natural Plants Compounds as Therapeutic Inhibitors Targeting RdRp and Nucleocapsid Proteins of SARS CoV 2: An in Silico Approach

“…It makes them into a helical capsid structure or ribonucleoprotein (RNP) complex. Because of this function, it is suggested that the corona virus N protein is an RNA chaperone and performs a main role in viral genomic RNA replication [14,15]. Our present study has been undertaken to compare binding a nity analysis of various natural plants compounds and small molecules against RdRp and Nucleocapsid Proteins of SARS COV 2 by using Molecular Docking Methods [16].…”