Abstract
BackgroundHepatitis C virus (HCV) is a global medical condition that causes several life-threatening chronic diseases in the liver. The conventional interferon-free treatment regimens are currently in use by a blend of direct-acting antiviral agents (DAAs) aiming at the viral NS3 protease. However, major concerns may be the issue of DAA-resistant HCV strains and the limited availability to the DAAs due to their high price. Due to this crisis, the developments of a new molecule with high potency as an NS3/4A protease inhibitor of the hepatitis-C virus remain a high priority for medical research. This study aimed to use in-silico methods to identify high potent molecule as an NS3/4A protease inhibitor and investigating the binding energy of the identified molecule in comparison with approved direct-acting antiviral agents (Telaprevir, Simeprevir, and Voxilaprevir) through molecular docking.ResultsThe model obtained by in-silico method have the following statistical records, coefficient of determination (r2) of 0.7704, cross-validation (q2LOO = 0.6914); external test set (r2(pred) = 0.7049) and Y-randomization assessment (cR2p = 0.7025). The results from the model were used to identify 12 new potential human HCV NS3/4A protease inhibitors, and it was observed that the identified molecule is well-fixed when docked with the receptor and was found to have the lowest binding energy of − 10.7, compared to approved direct-acting antiviral agents (Telaprevir, Simeprevir, and Voxilaprevir) with − 9.5, − 10.0, − 10.5 binding energy, respectively.ConclusionThe binding affinity (− 10.7) of the newly identified molecule docked with 3D structures of HCV NS3/4a protease/helicase (PDB ID: 4A92) was found to be better than that of Telaprevir, Simeprevir, and Voxilaprevir (approved direct-acting antiviral agents) which are − 9.5, − 10.0, and − 10.5, respectively. Hence, a novel molecule was identified showing high potency as HCV NS3/4a protease inhibitors.
Highlights
Hepatitis C virus (HCV) is a global medical condition that causes several life-threatening chronic diseases in the liver
Whichever molecule through SDR less than − 3 or greater than + 3 are labeled an outlier in the Results A QSAR method for investigating the structure–activity relationship of 63 HCV NS3/4a protease inhibitors variable response area, as well as any molecule with con- was implemented in the present research, and the QSAR trol higher value than h∗, is labeled a distinguished mol- model is presented as: ecule foreign to the most compounds used during model constpruICct5i0on=. −50.5082(±22.1927) − 0.0021(±0.0004)ATSC5i
Protein structure preparation The structure of HCV NS3/4a protease was extracted via Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) with the HCV NS3/4a protease structural PDB ID being 4A92
Summary
Hepatitis C virus (HCV) is a global medical condition that causes several life-threatening chronic diseases in the liver. Major concerns may be the issue of DAA-resistant HCV strains and the limited availability to the DAAs due to their high price Due to this crisis, the developments of a new molecule with high potency as an NS3/4A protease inhibitor of the hepatitis-C virus remain a high priority for medical research. As a cofactor, the central portion of NS4A is essential to offer NS3 with a fitted complex and stimulate the catalytic process. At these intersections, abnormalities in NS4A disrupt the NS3 protease to cleave. HCV GTs 5, 6, and 7 are perhaps the most geographically limited, with GT5 accessible in South Africa and GT6 common in eastern and southeastern Asia, whereas GT7 was stated in a small percentage of people in DR Congo (Coppola et al 2019; Rabaan et al 2019; Smith et al 2014)
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