Application of temperature-dependent and steered molecular dynamics simulation to screen anti-dengue compounds...

Marburg virus infections are extremely fatal with a fatality range of 23% to 90%, therefore there is an urgent requirement to design and develop efficient therapeutic molecules. Here, a comprehensive temperature-dependent molecular dynamics (MD) simulation method was implemented to identify the potential molecule from the anti-dengue compound library that can inhibit the function of the VP24 protein of Marburg. Virtual high throughput screening identified five effective binders of VP24 after screening 484 anti-dengue compounds. These compounds were treated in MD simulation at four different temperatures: 300, 340, 380, and 420 K. Higher temperatures showed dissociation of hit compounds from the protein. Further, triplicates of 100 ns MD simulation were conducted which showed that compounds ID = 118717693, and ID = 5361 showed strong stability with the protein molecule. These compounds were further validated using $\Delta G$ binding free energies and they showed: -30.38 kcal/mol, and -67.83 kcal/mol binding free energies, respectively. Later, these two compounds were used in steered MD simulation to detect its dissociation. Compound ID = 5361 showed the maximum pulling force of 199.02 kcal/mol/nm to dissociate the protein-ligand complex while ID = 118717693 had a pulling force of 101.11 kcal/mol/nm, respectively. This ligand highest number of hydrogen bonds with varying occupancies at 89.93%, 69.80%, 57.93%, 52.33%, and 50.63%. This study showed that ID = 5361 can bind with the VP24 strongly and has the potential to inhibit its function which can be validated in the in-vitro experiment.