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  • br Experimental br Acknowledgment br Introduction Hepatitis

    2021-09-11


    Experimental
    Acknowledgment
    Introduction Hepatitis C virus (HCV) belongs to Flaviviridae, is a blood-borne pathogen which infects about 180 million individuals throughout the world; most of the cases lead to end stage liver diseases, fibrosis, cirrhosis and hepatocellular carcinoma (Choo et al., 1989; Major and Feinstone, 1997; Wasley and Alter, 2000). About 10 million populations of Pakistan are infected with HCV, with rare cases of spontaneous clearness; most of them progress to chronic cases (Ali et al., 2016). The most prevalent genotype among eleven HCV genotypes in Pakistan is 3a (Waheed et al., 2009). For a decade pegylated interferon a (PEG-IFN-a) plus ribavirin (RBV) remained treatment of the choice, is expensive, associated with severe side effects and effective for certain genotypes (Dillon, 2004; Farci et al., 2006; Ferenci, 2006; Ni and Wagman, 2004; Reichard et al., 1998). Different treatment response pattern to HCV genotypes is due to the genetic heterogeneity of virus. Considerable variability is shown by the virus which directly interferes with the disease treatment. The response to treatment varies according to HCV genotype and subtype (Bastos et al., 2016). The sustained virological response rate (SVR) in Pakistani population infected with 3a genotype to IFN-α and RBV combination therapy is 87.5%, approximately 2.45% of the patients discontinued treatment due to adverse side effects (Ali et al., 2016). Lacking of efficient treatment regimens and increased incidence rate of HCV infection has created a pressure for the therapeutic compounds that can efficiently target the HCV (López-Labrador, 2008). Nonstructural protein NS3/NS4A serine protease and helicase are considered as potential drug targets for the development of effective anti-HCV compounds (Ashfaq et al., 2011). The main role of NS3/NS4A is to cleave viral poly protein into different mature proteins at various time intervals as well as involved in viral replication; HCV helicase affects the viral life how to calculate molarity at two steps for unwinding of double strand RNA intermediate required for the movement of HCV NS5B polymerase (Piccininni et al., 2002). NS3 structural analysis revealed a new function of HCV helicase as translocase and considered as a potential specific inhibitor to block NS3 helicase (Gu and Rice, 2010). For predication and comparison of molecular and physicochemical properties and mechanisms of reactions of different therapeutic compounds, molecular modeling techniques are widely used (Elfiky et al., 2013; Saleh et al., 2014). For HIV-1 and HCV proteases effective inhibitors are designed through these techniques (Elfiky et al., 2013; Ibrahim et al., 2012a; Ibrahim et al., 2012b). Computational studies not only motivated researchers for the identification of novel therapeutic targets but also fortify the drug designing/development process. The field of computational biology and its latest uses has offered reliable methods for the enhanced understanding of biological systems of interest (Azam et al., 2009a; Azam et al., 2009b, Azam et al., 2009c; Azam et al., 2010; Azam et al., 2012; Barreca et al., 1999; Cheng et al., 2002). In the current study, the potent NS3-3a protease inhibitors, previously designed for NS3, have been identified by employing different computational techniques such as homology modeling, and molecular docking.
    Methods
    Results and discussion
    Conclusion Computational approaches have been extensively used for the designing of potent small molecules against HCV. Three dimensional structures generated by employing homology modeling technique are extensively used in wide range of applications. In the present study, 3D structure of NS3 genotype 3a, constructed from HCV positive patient, was reported for the first time. Keeping in view the importance of protein-inhibitor interactions, we successfully identified a potent inhibitor against the generated model using molecular docking approach. Compound 1 (Table 2) predicted in the current study, showed high binding affinity against modeled protein. It was found binding deep inside the ATP binding site with few residues of helicase domain of NS3. It also developed hydrogen bond interactions unlike FDA approved (Telaprevir and Boceprevir) NS3 protease inhibitors. The study can serve as model to design dual antiviral inhibitors against other HCV genotypes in future.