Molecular modelling studies on adamantane-based Ebola virus GP-1 inhibitors using docking, pharmacophore and 3D-QSAR.

The pathogenic Ebola virus (EBOV) causes a potential health risk and global spread. To date, few drugs are available for the treatment of Ebola virus disease (EVD) that allow researchers to use computational methods for designing potential drugs. The developed PHASE-based common six-point pharmacophore hypothesis (AADHPR_1) showed the necessity of two hydrogen bond acceptor features, one hydrogen bond donor feature, one hydrophobic group feature, one positively ionizable and one aromatic ring feature for further designing. We developed best 3D-QSAR models with high regression coefficients for the training (r2>0.82) and test (Q2>0.5) sets for both atoms-based and field-based 3D-QSAR models. The molecule 1A-4 (docking score = -4.711 kcal/mol) was obtained as best docked (SP mode) on Ebola virus envelope glycoprotein (PDB ID-3CSY) as compared with the standards oseltamivir (docking score = -4.39 kcal/mol) and zanamivir (docking score = -3.392 kcal/mol). The obtained ZINC hit ZINC58935541 showed a good docking score of -4.892 kcal/mol. The ZINC58935541 molecule also showed a strong binding affinity towards the receptor cavity of Ebola virus envelope glycoprotein when simulated for 1.2 ns. The good QikProp parameters reflect the fact that this molecule, upon optimization into a lead, might become a good candidate for the treatment of EVD.