Ligand and Structure-Based Pharmacophore Modelling, Computer-aided Screening and Molecular Docking to Detect Novel NS5B Polymerase Inhibitors as Anti-HCV Compounds

Abstract

The ongoing interest of researchers in the direct-acting NS5B inhibitors in the development of viral disease hepatitis has attracted our attention in the direction of the development of a quantitative four-featured pharmacophore model containing HBA (2), HY (1), and PI (1) features. The model showed correlation coefficient, RMSD, and cost difference values as 0.895, 0.911, and 30.896, respectively. The model validation is done by using Fisher's randomization test (99%), internal and external tests set the expectation with r2 values of 0.80 and 0.65. Simultaneously, the 3D crystal structure of NS5B was utilized for generating a pharmacophore model design based on a structure with features generation 2 Hydrogen Bond Acceptors, 2 Hydrogen Bond Donors, and 2 Hydrophilic features. Further on these two models, HITS searches using NCI and Maybridge databases were done. Three hundred forty-five compounds were screened, and the three greatest potent hits were docked to the active site of NS5B. It was found that these docked conformations showed interactions with GLN446 and TYR448 amino acids, which are located at NS5B active site. In an instant, with the use of various computational methods in a sequence, we have identified novel structurally diverse NS5B inhibitors.