NS3 protein is highly conserved among all the four antigenically different serotypes of Dengue virus (DENV) and has an indispensable role in viral replication. Fifty-four molecules identified using GC-MS analysis from methanolic seeds extract of Foeniculum vulgare were subjected to ADMET profiling using SwissADME and ProTox 3.0 webserver. Twenty-eight molecules followed all Lipinski's rules and were predicted to cross blood brain barrier (BBB) with high gastro-intestinal absorption. Docking with NS3 protein of DENV-4 revealed that molecule 12 (Fenchyl acetate) and molecule 14 (Dillapiol) were involved in stabilizing hydrogen bond formation with Arg387, Thr408 and Val544, Arg599, respectively. These conserved residues are directly involved in RNA binding and tunnel formation to accommodate RNA. Docked complexes were investigated at atomic level for their structural stability through MD simulations. RMSD and RMSF trajectory of NS3-molecule 12 showed minimum structural deviation as compared to NS3 protein and NS3-molecule 14 complex. PCA of NS3-molecule 12 complex showed decreased collective motion occupying similar but reduced conformational space compared to NS3 and NS3-molecule 14 complex. Rg plot of NS3-molecule 12 complex showed comparatively lower dissociation and more rigid structure. PCA and FEL analysis revealed that NS3-molecule 12 complex had comparatively more energetically favored and thermodynamically stable conformational state. Total Gibbs free energy and contribution of different interactions calculated using MMGBSA further validated the docking results. These findings provide a foundation for F. vulgare derived therapeutic interventions against Dengue fever. Thus, Fenchyl acetate showing no predicted toxicity and Dillapiol, within its predicted LD50 concentration can be further studied for experimental validation.
Tazeen et al. (Sat,) studied this question.