Abstract
Hepatitis C Virus (HCV) is a leading cause of cirrhosis and liver cancer worldwide. The replication and viral polyprotein maturation of HCV crucially depends on the cleavage of the polyprotein precursor into 10 viral proteins. The NS3-4A serine protease cleaves the nonstructural region of the polyprotein at four out of five junctions, thus is a promising target for the development of antiviral inhibitors. There are many inhibitors of HCV NS3/4A protease in the clinical trial and improvement indicating significant reduction in the viral infection rate. However, most PIs develop resistance associated variants while treatment and are restricted to one or two HCV genotypes. The second generation PI, MK-5172, is the only exception, which potently inhibits most variants associated with resistance to first generation PIs and is pan-genotypic. In this study, we investigated the potent lead compound(s) based on similarity search using the most potent proved protease inhibitor, MK-5172. We have performed virtual screening techniques using PubChem database available in NCBI to identify lead like molecules. The database has yielded 32 hits for 95% similarity search and the pharmacokinetic analysis (ADME) was performed for screened compounds. This structure based drug design identified three lead compounds that can work better against NS3/4A protease.
Highlights
Hepatitis C virus (HCV) infects an estimated 200 million people worldwide
In silico ligand-based Virtual Screening result indicates that 32 compounds were identified for NS3-4A protease inhibition, similar to the currently active drug molecule, MK-5172
There is no specific vaccine for HCV till and the available standard therapy of Peg-IFN/Ribavirin is associated with many side effects, there has been substantial progress in the research work and clinical improvement of novel antiviral drugs
Summary
Hepatitis C virus (HCV) infects an estimated 200 million people worldwide. About 3% of the world’s population is chronically infected with HCV and 3-4 million people are newly infected each year [1], often leading to cirrhosis, hepatic failure, and hepatocellular carcinoma. Hepatitis C virus (HCV) is an enveloped RNA virus which belongs to the Flaviviridae family and is the unique member of the Hepaci virus genus with at least 6 genotypes and numerous subtypes [2,3]. Efficient vaccine against HCV does not exist and the only available standard therapy is a combination of pegylated interferon- α (IFN-Peg) and ribavirin, efficient in only 50% of patients chronically infected [4]. IFN α/Ribavirin helps in controlling the viral outbreak inside hosts, these are indirect antivirals and do not target a specific HCV protein or RNA element. Direct-acting antiviral agents (DAA) have the potential to improve Sustained virologic response (SVR) rates and minimize treatment duration
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