Targeting Ebola Virus VP30 with Quercetin Derivatives: An Integrated Molecular Docking, MD Simulation, ADMET, and DFT Study
TL;DR
D1 and D2 derivatives have good drug-like and safety profiles, while their bioavailability is moderate with the possibility of nephrotoxicity, and density functional theory calculations showed that both analogues have favorable electronic structures, such as a low HOMO-LUMO gap and lowest unoccupied molecular orbital, respectively.
Abstract
Ebola virus disease still poses a major threat to global public health because of its high case-fatality ratio and lack of antiviral medicines. Therefore, in this study, seventeen quercetin derivatives (D1-D17) were computationally screened against the Ebola virus VP30 protein, which acts as a transcription activator in the Ebola virus life cycle. D1 and D2 derivatives displayed high binding energies (–9.1 and –8.7 kcal mol-1, respectively), showing the formation of hydrogen bonding, π-sigma, and π-alkyl interactions with the vital amino acid residues in VP30 protein. Stability of the complexes was further assessed by conducting molecular dynamics simulation for 100 ns based on root mean square deviation, root mean square fluctuation, radius of gyration, principal component analysis, and molecular mechanics/poisson-Boltzmann surface area calculations. The results revealed that VP30-D1 and VP30-D2 complexes exhibited high binding free energies with the values of –22.1562 and –19.7180 kcal mol-1, respectively. The pharmacokinetic and safety analysis predicted that D1 and D2 have good drug-like and safety profiles, while their bioavailability is moderate with the possibility of nephrotoxicity. Density functional theory calculations showed that both analogues have favorable electronic structures, such as a low HOMO-LUMO gap (highest occupied molecular orbital and lowest unoccupied molecular orbital, respectively), electrophilicity index, and high electron delocalization.