Abstract
Dengue virus (DENV) infection causes serious health problems in humans for which no drug is currently available. Recently, DENV NS2B-NS3 protease has been proposed as a primary target for anti-dengue drug discovery due to its important role in new virus particle formation by conducting DENV polyprotein cleavage. Triterpenoids from the medicinal fungus Ganoderma lucidum have been suggested as pharmacologically bioactive compounds and tested as anti-viral agents against various viral pathogens including human immunodeficiency virus. However, no reports are available concerning the anti-viral activity of triterpenoids from Ganoderma lucidum against DENV. Therefore, we employed a virtual screening approach to predict the functional triterpenoids from Ganoderma lucidum as potential inhibitors of DENV NS2B-NS3 protease, followed by an in vitro assay. From in silico analysis of twenty-two triterpenoids of Ganoderma lucidum, four triterpenoids, viz. Ganodermanontriol (−6.291 kcal/mol), Lucidumol A (−5.993 kcal/mol), Ganoderic acid C2 (−5.948 kcal/mol) and Ganosporeric acid A (−5.983 kcal/mol) were predicted to be viral protease inhibitors by comparison to reference inhibitor 1,8-Dihydroxy-4,5-dinitroanthraquinone (−5.377 kcal/mol). These results were further studied for binding affinity and stability using the molecular mechanics/generalized Born surface area method and Molecular Dynamics simulations, respectively. Also, in vitro viral infection inhibition suggested that Ganodermanontriol is a potent bioactive triterpenoid.
Highlights
Dengue virus (DENV) belongs to the Flaviviridae family and is a lethal microbe, transmitted by Aedes albopictus and Aedes aegypti mosquitoes[1,2,3], which causes Dengue Hemorrhagic Fever[4,5] and Dengue Shock Syndrome[6,7]
Antiviral activity of G. lucidum triterpenoids have been documented against various pathogenic viruses such as herpes simplex virus types 1 (HSV-1 and HSV-2), influenza A virus (Flu A), vesicular stomatitis virus (VSV) and human immunodeficiency virus (HIV)[24,36,37]
Considering the important role of NS2B-NS3 protease in DENV infection, identification of bioactive triterpenoids from G. lucidum that can inhibit NS2B-NS3 protease activity was proposed as an essential step towards the discovery of DENV inhibitors
Summary
The NS3pro-Ganoderic acid C2 complex exhibited contributions of Lys[28], Ile[36], Trp[50], His[51], Arg[54], Val[72], Lys[74], Asp[75], Leu[128], Asp[129], Phe[130], Ser[131], Pro[132], Ser[135], Tyr[150], Gly[151], Asn[152], Gly[153], Val[155] and Tyr[161] residues in different molecular interactions in the protein-ligand mapping during the simulation (Fig. 6c). Major intermolecular interaction was contributed by Arg[54] through hydrogen bond formation followed by water bridges and ionic attraction (Fig. 6c) This residue was predicted in the molecular docking analysis to form two hydrogen bonds with Ganoderic acid C2 (Fig. 3e,f), suggesting that it is a key factor for maintaining target-ligand stability during the simulation. It was again suggested that these triterpenoids could be used in the formulation of drugs DENV infection
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