الفهرس 
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Abstract
In this project an attempt has been done to interpret and support experimental findings regarding inhibition mechanism for Hepatitis C virus (HCV) non-structural-5b enzyme (NS5b). Twenty five inhibitors for HCV NS5b were docked by QM-Polarized Ligand Docking (QPLD) technique. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used to derive three dimentional (3D)-quantitative structure activity relationship (QSAR) models for the selected inhibitors. The CoMFA and CoMSIA models show good crossvalidated (Q2) and non-cross-validated (R2) coefficients for the suggested inhibitors of 0.43, 0.98 and 0.65, 0.99, respectively. The inhibition mechanism was explored and validated. Details of the interactions between the inhibitors and HCV NS5b are given in terms of steric, electrostatic, hydrophobic, hydrogen bonding fields. Enhancing potency via substitutions at particular positions was explored based on these parameters. A good correlation was found between 3D-QSAR and docking results. Receptor based approaches have been applied to novel ten HCV NS5b inhibitors. The study elucidate, the binding mode of Non-nucleoside and nucleoside analogue inhibitors to the crystal structure of HCV NS5b (2HAI) by means of molecular docking. Docking protocol with both restricted electrostatic potential (RESP) charges and Gasteiger charges were performed. The docking study confirmed that non-polar hydrophobic (Leu419), polar hydrophilic (Ser 476) and positively charged polar (Arg501) residues were important interaction sites in Thumb domain of the polymerase. These novel compounds show high activity towards allosteric sites and active site, when applying RESP charges for Non-nucleoside inhibitors and bad influence for nucleoside analogue inhibitors. Experimental work was applied to prepare one of the ten novel HCV NS5b inhibitors.