Discovery of Small Molecules from Echinacea angustifolia Targeting RNA-Dependent RNA Polymerase of Japanese Encephalitis Virus

Abstract

The Japanese encephalitis virus (JEV), a mosquito-borne flavivirus that causes viral encephalitis leading to neural damage, is a major threat in most Asian countries. The RNA-dependent RNA polymerase (RdRp) present in the viral genome is the key component for genome replication, making it an attractive target for antiviral drug development. In this study, the natural products from Echinacea angustifolia were retrieved for structure-based virtual screening against JEV–RdRp. The top six compounds (Echinacoside, Echinacin, Rutin, Cynaroside, Quercetagetin 7-glucoside, and Kaempferol-3-glucoside) were obtained based on the highest negative docking score, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and molecular interaction. The computational analysis of these selected compounds against the co-crystallized ligands, i.e., ATP and GTP, were performed. Further, 100 ns molecular dynamic simulation and post-free binding energy calculation of all the selected compounds complexed with JEV–RdRP were performed to check the stability of the complexes. The obtained results showed considerable stability and intermolecular interaction with native ligand-binding site residues of JEV–RdRp. Hence, selected natural compounds are admissible inhibitors of JEV–RdRp protein and can be considered for future antiviral drug development studies.

Marine Brown Algae-Derived Compounds as Potential Inhibitors of Japanese Encephalitis Virus RNA-Dependent RNA Polymerase

“…Interestingly, the RMSD analysis of the selected compound has remarkable dynamic stability. A similar situation was observed with compounds obtained from Azadicrachta indica, and Echinacea angustifolia docked with JEV-RdRp protein [31,32]. These findings confirm that the ligand molecules are also in a stable conformational state during the simulation.…”

“…For instance, Dwivedi and his co-workers discovered natural inhibitors from Azadirachta indica against RdRp, with compounds like Gedunin, Nimbolide, Ochinin acetate, and Kulactone showing docking scores ranging from −10.4 to −11.0 kcal/mol [31]. Similarly, Yadav and his team identified potent phytocompounds such as Echinacoside and Kaempferol-3-glucoside from Echinacea augustifolia, chosen for their high negative docking scores [32]. These studies confirm that natural compounds have the substantial potential to be promising inhibitors of RdRp protein.…”

Pharmacological Properties and Safe Use of 12 Medicinal Plant Species and Their Bioactive Compounds Affecting the Immune System

“…Similar results were observed using an aqueous extract (at the same concentration). In contrast, the chloroform fraction stimulated phagocytosis at a tenfold lower concentration by 34% [30].…”

“…The characteristic compounds of Echinaceae purpureae herba recens are alkylamides (alkamide complex), polysaccharides (4-O-methylglucuronoarabinoxylan, arabinorhamnogalactate acid), and glycoproteins. The chemical structure and the immunostimulating effect of alkylamides and other natural compounds are presented in Table S1 [26][27][28][29][30][31][32][33][34][35][36][37][38]. Meanwhile, in Figure 1, the scheme demonstrating the postulated molecular mechanisms of action of plant-derived immunomodulators is presented.…”

Recent Advances in Antivirals for Japanese Encephalitis Virus

“…Few JEV NS5-targeting drugs have been validated at the cellular or animal level practically, and several compounds that characteristically target the JEV NS5 remain in the early stages of in silico studies. Several compounds, including echinacoside, echinacin, rutin, cynaroside, quercetagetin 7-glucoside, and kaempferol-3-glucoside, have been shown to theoretically bind to JEV NS5 RdRp [ 64 ]. In addition, four bioflavonoid compounds, gedunin, nimbolide, ohchinin acetate, and kulactone, have been theoretically demonstrated to be capable of binding to the active site of JEV NS5 RdRp [ 65 ].…”