Flexible docking-based molecular dynamics simulation of natural product compounds and Ebola virus Nucleocapsid (EBOV NP): a computational approach to discover new drug for combating Ebola

Abstract

Background: Ebola still remains as one of the most problematic infectious diseases in Africa with a high rate of mortality. Although this disease has been known for an almost half-century, there are no vaccines and drugs available in the market to treat Ebola. Zaire ebolavirus (EBOV), a single-stranded RNA virus which belongs to Filoviridae family and Mononegavirales order, is one of the virus causing Ebola. As one of seven proteins that EBOV encodes, Ebola virus nucleoprotein (EBOV NP) plays an imperative role in EBOV proliferation cycle. Therefore, the development of a new Ebola treatment can be targeted towards EBOV NP.

Results: In this work, we screened about 190,084 natural product compounds from ZINC15 database through in silico virtual screening and flexible docking simulation. Furthermore, the bioavailability and toxicity prediction have been conducted as well. Two best ligands according to the simulation and prediction tests were progressed into the molecular dynamics simulation.

Conclusion: In the end, we found that our proposed ligands, namely α-lipomycin (ZINC56874155) and 3-(((S)-1-amino-1,2,3,4-tetrahydroisoquinolin-5-yl)methyl)-5-((5-((5R,7S)-5,7-dihydroxy-3-oxodecyl)-2-hydroxyphenoxy) methyl)pyrrolo[3,4-b]pyrrol-5-ium (ZINC85628951), showed the promising results to be developed as a lead compounds for treating Ebola. Therefore, an experimental study is required to validate their inhibition activities against EBOV NP.

Keywords: Ebola virus; Ebola virus nucleocapsid; Flexible docking; Molecular dynamics simulation; Natural product compounds; Virtual screening.

Fig. 1

Research flowchart that was used in this study. The number inside the circles mark the number of ligands that have been used in the respective step

Fig. 2

The 3D structure of Ebola nucleocapsid (NP) taken from PDB ID: 4Z9P (left), along with the binding site of EBOV NP (RNA-binding groove) according to Fu et al. in 2016

Fig. 3

The 3D (left) and 2D (right)molecular interaction between RNA-binding groove of EBOV NP with Licochalcone A (top) and 18β-Glycyrrhetinic Acid (bottom)

Fig. 4

The 2D (left) and 3D (right) molecular interaction between RNA-binding groove of EBOV NP with α-lipomycin ligand (top), ZINC85596639 ligand (center), and ZINC85628951 ligand (bottom)

Fig. 5

The RMSD curve from molecular dynamics simulation at 20 ns (20.000 ps). The x-axis represents the simulation time (at ps), while the y-axis represents the RMSD value (at nm).

Fig. 6

The 3D (top) and 2D (bottom) molecular interaction between EBOV NP and ZINC85628951 at the RNA-binding groove after equilibration process (left), when 10 ns (center), and 20 ns (right) dynamics simulation was occurred