Ebola virus envelope glycoprotein derived peptide in human Furin-bound state: computational studies.

Ebola virus (EboV) is currently ravaging West Africa with estimated case fatality rate of 52%. Currently, no drug treatment is available and immunoglobulin therapy is still at the rudimentary stage. For anti-EboV drug development, druggable viral and host protein targets, including human Furin are under intense investigation. Here, molecular dynamics simulation was performed on Apo-Furin, meta-guanidinomethyl-Phac-RVR-Amba-bound, and two EboV glycoprotein (GP) 494-TGGRRTRREA-503/Furin complexes (Accurate and one amino acid shift alignment). The results of the simulation established ligand-induced desolvation of Furin active site and structural compactness. Accurately aligned EboV-GP peptide exhibited a tighter binding mode with Furin and showed 1.5- and 3.0-fold MMPBSA binding free energy estimate compared with the displaced peptide and inhibitor, respectively. The difference in free energy was traced to the difference in contribution of threonine residues of the peptides. Furthermore, Furin subsites I conferred substrate specificity and ligand binding accuracy. Accurately aligned peptide trapped active site His194 side chain into gauche (-) (+60(o)) χ1-dihedral compared with gauche+ (-60(o)) in other biosystems while Asp153 is trapped in gauche+ (-60(o)) in ligand bound not Apo state. Ramachandran plot showed that the scissile Arg8 of the accurately aligned peptide showed β conformation distribution as apposed to 310R, αL, and 310L. Finally, the active site proximal Na(+) binding is dependent on substrate peptide occupancy of the active site but detaches in the absence of a ligand. In conclusion, Furin might represent candidate drug target for Ebola virus disease treatment via therapeutic target of the active site and Na(+) binding pocket.