Discovery of Ganoderma lucidum triterpenoids as potential inhibitors against Dengue virus NS2B-NS3 protease

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.

SARS-CoV-2 Mproinhibitors: identification of anti-SARS-CoV-2 Mprocompounds from FDA approved drugs

“…ΔG Bind Coulomb , ΔG Bind Covalent , ΔG Bind Hbond , ΔG Bind Lipo (hydrophobic interactions), ΔG Bind Solv GB (Generalized Born electrostatic solvation energy), ΔG Bind packing (π–π interactions), and ΔG Bind vdW (van der Waals energy) revealed significant contribution of ΔG Bind Coulomb and ΔG Bind vdW energy in the respective complex stability (Table S4, Figures 8 and S15 ), supports the favorable enthalpy formation in the respective complexes. Similar results for the energy components ΔG Bind Coulomb and ΔG Bind vdW contributing in the docked complexes were reported earlier ( Bharadwaj et al., 2019 ). Moreover, no significant contribution of ligand strain energy was observed in all the complexes, indicates the considerable affinity of screened drugs by comparison to N3 inhibitor with the active pocket of SARS-CoV-2 M pro .…”

“…Thereof, the selected SARS-CoV-2 M pro -screened drug complexes were monitored for the docked complex stability under 100 ns MD simulations conducted in Desmond suite. The produced MD trajectory for each docked complex were scrutinized in terms of last snapshot of simulated docked complex, root mean square deviation (RMSD), root mean square-fluctuations (RMSF), and protein-ligand contacts mapping with respect to 100 ns interval, as reported earlier ( Bharadwaj et al., 2019 ).…”

Computational insights into tetracyclines as inhibitors against SARS-CoV-2 Mpro via combinatorial molecular simulation calculations

“…The molecular docking algorithms have been widely used to predict the bioactive compounds or drug repurposing against various drug targetable proteins in diseases and infections [36,47]. Likewise, this study also employed the molecular docking simulation approach for the selected antibiotic tetracyclines, i.e.…”

“…Molecular dynamics simulation can be employed to the docked complexes to study their stability and intermolecular interaction profiling with respect to time [47,48]. In this study, docked complexes of antibiotics and N3 inhibitor with viral protease were subjected to 100 ns molecular dynamics (MD) simulation to predict the respective complex confirmation change, stability, and intermolecular interactions between the active residues of the receptor and atoms of the ligand molecules.…”

Structural basis for the inhibition of SARS-CoV2 main protease by Indian medicinal plant-derived antiviral compounds

“…About 25,000 plant-based formulations have been used in folk remedies in Indian medicine (Adhikari & Paul, 2018 ). Owing to their use in traditional medicine, many plant molecules have been studied and subsequently modulated into drugs for various diseases (Bharadwaj et al., 2019 ; Dwivedi et al., 2020 ; Fabricant & Farnsworth, 2001 ; Li-Weber, 2009 ).…”