Structure-based identification of dual targeting lead inhibitor to Marburg virus glycoprotein and Chandipura virus nucleoprotein: Insights from molecular docking, dynamics and binding free energy analyses

Abstract

Marburg virus (MARV) and Chandipura virus (CHPV), belonging to the families filoviridae and rhabdoviridae, respectively, are RNA viruses producing a hemorrhagic fever and severe encephalitis with a high mortality rate. The present study computationally explores the antiviral potential of bioactive molecules from Glycyrrhiza glabra (Licorice root) against the glycoprotein (GP) of MARV and nucleoprotein (NP) of CHPV. The 3D structures of GP and NP are not available in their native forms, and these structures were computationally modelled and validated for their structural and stereochemical properties. Licorice compounds with satisfactory pharmacokinetics such as drug likeness and ADMET, were docked against these targets, and comparison was made with the docking results of the reference antiviral drug, favipiravir and the target VP35 by using their binding affinities. Apigenin possessed the highest binding affinity with GP and NP at −6.3 and −7.1 kcal/mol, respectively, with greater binding affinities compared to favipiravir and VP35 at −4.2 kcal/mol. Additional stability of apigenin-protein complexes was investigated by MD simulations, including RMSD, RMSF, H-bonds, PCA, FEL, and DCCM analyses. These revealed a stable conformational stability and interaction formation in apigenin-protein complexes, however, apigenin-GP complex was found more stable than apigenin-NP. Binding free energy calculations, conducted using MM/GBSA and MM/PBSA, also estimated ΔG values of −679.65 kcal/mol and −92.30 kcal/mol for apigenin-GP and apigenin-NP complexes. This in silico model highlights apigenin from Glycyrrhiza glabra as a potential dual targeting antiviral therapeutic against both CHPV and MARV, and finds significant applications in further in vitro and in vivo validation.