Evaluation of the Antiviral Potential of Halogenated Dihydrorugosaflavonoids and Molecular Modeling with nsP3 Protein of Chikungunya Virus (CHIKV)

Abstract

Antiviral therapy is crucial for the circumvention of viral epidemics. The unavailability of a specific antiviral drug against the chikungunya virus (CHIKV) disease has created an alarming situation to identify or develop potent chemical molecules for remedial management of CHIKV. In the present investigation, in silico studies of dihydrorugosaflavonoid derivatives (5a–f) with non-structural protein-3 (nsP3) were carried out. nsP3 replication protein has recently been considered as a possible antiviral target in which crucial inhibitors fit into the adenosine-binding pocket of the macrodomain. The 4′-halogenated dihydrorugosaflavonoids displayed intrinsic binding with the nsp3 macrodomain (PDB ID: 3GPO) of CHIKV. Compounds 5c and 5d showed docking scores of −7.54 and −6.86 kcal mol–1, respectively. Various in vitro assays were performed to confirm their (5a–f) antiviral potential against CHIKV. The non-cytotoxic dose was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and was found to be <100 μM. The compounds 5c and 5d showed their inhibitory potential for CHIKV, which was determined through cytopathic effect assay and plaque reduction assay, which show inhibition up to 95 and 92% for 70 μM concentration of the compounds, respectively. The quantitative real-time polymerase chain reaction assay result confirmed the ability of 5c and 5d to reduce the viral RNA level at 70 μM concentration of compounds to nearly 95 and 93% concentration, respectively, in cells with CHIKV infection. Further, the CHIKV-inhibitory capacity of these compounds was corroborated by execution of immunofluorescence assay. The executed work will be meaningful for the future research of studied dihydrorugosaflavonoids against prime antiviral entrants, leading to remedial management to preclude CHIKV infection.

Synthesis of Novel Halogenated Heterocyclic compounds and their uses as Target SARS-CoV-2 main Protease (Mpro) and Potential Anti-Covid-19

“…As reflected from the figure, thethree halogenated compounds reside in the active site pocket of the SARS-CoV-2 M pro , superimposed over Nelfinavir suggesting the same mode of interaction, hence possible inhibition of the main protease of SARS-CoV-2. These results are in support of previous studies on the effectiveness of halogen-containing compounds as potential antiviral agents[63,64].…”

(ADP-ribosyl)hydrolases: structure, function, and biology

“…Together, these findings lead to the suggestion that targeting of viral macrodomains is a promising antiviral strategy. The hypothesis gained support recently by the development of dihydrorugosaflavonoid derivatives as inhibitors of the nsP3 macrodomain and the demonstration that these compounds are effective in reducing viral RNA levels in the infected cells (Puranik et al 2019).…”

In Vitro and In Silico Anti-Arboviral Activities of Dihalogenated Phenolic Derivates of L-Tyrosine

“…It has been reported that a distance of <2.9 Å between the donor group and the acceptor atom is favorable for hydrogen bond formation [ 48 ], and therefore is likely that the favorable nature of the interaction between the compounds (TDC-2M-ME and TDB-2M-ME) and the viral proteins is primarily caused by hydrophobic interactions rather than the hydrogen bonds ( Figure 6 , Table S1 ). These in silico results could explain the decrease in genome copies in the CHIKV/Col cultures treated with TDC-2M-ME and TDB-2M-ME ( Figure 3 A) because it has been described that NSP3 inhibition truncates viral replication [ 49 ] and that helicase function is essential to this process [ 32 ]. Future in vitro evaluations will help to further elucidate these hypotheses.…”