Interactions of ketoamide inhibitors on HCV NS3/4A protease target: molecular docking studies

Abstract

HCV infection in more than 200 million individuals worldwide is a principal health problem. Prior to the development of HCV protease inhibitor combination therapy, HCV infected patients were treated with pegylated interferon-α and ribavirin. The adverse side effects associated with this type of treatment may lead to the discontinuation of treatment in certain number of patients. Currently, the inhibitors of NS3/4A Protease were found promising candidates for the treatment of HCV infection. There are several inhibitors of HCV NS3/4A protease that are passing through clinical improvement showing good potency against HCV infections in a number of patients. To further recognize binding interactions and activity trend, the molecular docking studies were performed on a number of HCV NS3/4A protease ketoamide inhibitors via MOE docking protocol. The docking analysis resulted in the detection of important ligand interactions with respect to binding site of target protein and produced good correlation coefficient (r2 = 0.690) between docking score and biological activities. These molecular docking results should, in our view, contribute for further optimization of ketoamide derivatives as NS3/4A protease inhibitors.

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“…The binding mode of the ligands into the binding pocket of protein molecule was predicted by MOE-Dock implemented in MOE. After the completion of docking we analyze the best poses for Hydrogen Bonding/π-π interactions by using MOE applications 32 . All compounds were dissolved in methanol and experiments were performed in triplicate (mean ± sem, n = 3).…”

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“…The crystal structure coordinates of the receptors were loaded into Discovery Studio 4 software (DS4, Discovery Studio version 2.5, Accelrys Inc., CA, 2009) in the default form for linear structure models and docked with rhein. The ligand molecule of rhein was prepared by ChemBio Draw Ultra 12.0 software as a PDB format, then an energy minimization optimization was carried out, and the optimized conformation was used for docking with the receptors [13]. In brief, the structure of rhein was imported into the dock ligands modeler of DS4 software, and then was aligned to the prepared protein, the most stable structure was selected by the energy score.…”