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  • br Conclusion The addition of

    2021-11-30


    Conclusion The addition of 5 alpha reductase to natural substrate increases the number of H-bonds which indicates an increase in the stability of the docking systems. The investigated compounds are more stable than natural substrate in docking systems, where the natural substrate has two H-bonds while the investigated compounds have four or five H-bonds. The binding energy of suggested compounds is lower than that for natural substrate except for the compound with position 3. The functionality of dimer cellulose with the natural substrate resulted in an increase in the total energy values of the final docking system. The total energy values of docking system for the compound with position 6 and position 6′ (479.75Kcal/mol and 496.11Kcal/mol respectively) are close to the total energy value of the docking system of natural substrate (400.38Kcal/mol). On the other hand, the total energy values of the rest of the docking systems are increased from the total energy value of the docking system for the natural substrate. The investigated compounds (except the compound with position 3′) form more than one H-bond with HCV NS3 protease. The compound with position 3′ and the natural substrate form only one H-bond with HCV NS3 protease. Cellulose plays an important role in the mode of interaction with the HCV NS3 protease. Generally, the compounds with the cellulose modified by adding the natural substrate at positions 2, 2′, 3, 3′, 6 or 6′ enhance the docking activity and binding affinity of suggested compounds and are predicted to have enhanced HCV NS3 inhibitory activity than the natural substrate. Specially, the compound with position 6, can be considered a promising NS3 protease inhibitor. It has the lowest total energy value of docking system (479.75Kcal/mol), forms two H-bonds with HCV NS3 protease active site residues and is more stable in interaction system (five H-bonds within itself). Finally, in the docking system, the compound with position 6 has the lowest binding energy (−114.93Kcal/mol). Although this compound forms only H-bonds, its binding energy is the lowest and the binding affinity is the highest in this study. This means that there are possibly hydrophobic interactions as well as hydrophilic interactions (H-bonds) with the residues in HCV NS3 protease active site which increase the binding affinity.
    Funding This study received no fund and was not funded by any one.
    Conflict of interest
    Ethical approval
    Approximately 185 million people worldwide are estimated to be infected with hepatitis C virus (HCV), a small, enveloped, positive strand RNA virus., HCV is a major cause of chronic liver diseases such as cirrhosis and hepatocellular carcinoma. Moreover, in the U.S., this virus has been the leading cause of liver transplant. The early standard of care, a combination of peg-interferon-α and ribavirin, was an important milestone in patient care. However, this approach ultimately proved only moderately effective in treating the disease and was associated with side effects, some of which were significant and prompted discontinuation of treatment., , In an effort to provide interferon-free therapy, drug discovery efforts have been focused on the procurement of a direct-acting antiviral cocktail. Toward this end, small molecule discovery programs targeting the essential viral proteins NS3 protease, NS5A and NS5B have been studied extensively. Our efforts in the NS3 protease arena led to the discovery of a potent series of acyl sulfonamide-based tripeptidic inhibitors. BMS-605339 (, ) advanced to the clinic and demonstrated a significant antiviral response with a 1.8 log reduction in viral load after a single, 120 mg dose. However, further development of this compound was suspended due to a cardiovascular (CV) signal observed in patients receiving the drug. The CV liability associated with was resolved in the discovery process that ultimately provided asunaprevir (, ). The combination regimen of asunaprevir with the NS5A inhibitor daclatasvir (, ) was approved in Japan in July of 2014 for the treatment of patients with genotype (GT) 1b HCV infection.