Molecular interaction of the antiviral compound CW-33 and its analogues with the NS2B-NS3 protease of the Japanese encephalitis virus

In a previous study from our group, a novel compound, namely CW-33 (ethyl 2-(3′,5′-dimethylanilino)-4-oxo-4,5-dihydrofuran-3-carboxylate) was identified that exhibited antiviral activity for Japanese encephalitis virus (JEV). The viral NS2B-NS3 serine protease serves an important role in cytoplasmic cleavage events that occur during viral polyprotein maturation. The inhibition of viral RNA and protein syntheses was responsible for the antiviral activities of the novel furanonaphthoquinone derivatives that were discovered for the prevention of JEV infection. Consequently, the present study examined the molecular docking simulation of JEV protease with compound CW-33 and its analogues, and developed quantitative structure-activity relationship (QSAR) models to assess the potential antiviral activities of these compounds with regard to JEV. Molecular docking simulation indicated the potential ligand-protein interactions associated with the antiviral activities of these compounds. According to the results of the QSAR models, the secondary amine group was an important moiety required for compound bioactivity, which enabled the formation of hydrogen bonding with the residue Glu155. Furthermore, the aromatic ring mapping of the phenyl moiety of each compound was predicted to form a π-cation interaction with residue Arg76, whereas the hydrophobic feature represented by the ethyl moiety exhibited hydrophobic contacts with residue Glu74. Finally, the hydrophobic substituents in the meta-position of the phenyl ring further contributed to the efficacy of the antiviral activity. These results unravel the structural characteristics that are required for binding of CW-33 to the JEV protease and can be used for potential therapeutic and drug development purposes for JEV.