Identification of potential anti‐hepatitis C virus agents targeting non structural protein 5B using computational techniques

• Published in: Journal of cellular biochemistry 2018-11, Vol.119 (10), p.8574-8587
• Main Authors: Polamreddy, Prasanthi, Vishwakarma, Vinita, Saxena, Puneet
• Format: Article
• Language: English
• Subjects: Allosteric properties; Allosteric Site; Antiviral Agents - chemistry; Antiviral Agents - therapeutic use; Beneficial use; Computational Biology - methods; Computational chemistry; Computer applications; Disease; DNA-directed RNA polymerase; Drug discovery; Drug Repositioning - methods; drug repurposing; Fatty liver; Fluvastatin; Fluvastatin - chemistry; Fluvastatin - metabolism; Fluvastatin - therapeutic use; Gene set enrichment analysis; Hepacivirus - enzymology; Hepatitis; Hepatitis C; Hepatitis C - drug therapy; Hepatitis C - genetics; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Ligands; Lipids; Liver; Liver diseases; Metabolic Networks and Pathways - genetics; Molecular Docking Simulation; Molecular Dynamics Simulation; Nonstructural protein 5B; nonstructural protein 5B (NS5B); Olopatadine; Olopatadine Hydrochloride - chemistry; Olopatadine Hydrochloride - metabolism; Olopatadine Hydrochloride - therapeutic use; Organic chemistry; Protein Binding; Protein Structure, Secondary; Proteins; Ribonucleic acid; RNA; Transcriptome; User-Computer Interface; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viruses
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.27071

Hepatitis C virus (HCV) nonstructural protein 5B (NS5B) is an RNA‐dependent RNA polymerase that plays a key role in HCV replication, and, hence, NS5B is an attractive target for hepatitis C drug discovery. Hepatitis C is a chronic liver disease affecting the global population significantly. Many NS5B inhibitors targeting active site were launched in recent years, however, still there exists a pressing need for cost‐effective therapies with pan genotypic activity and therapies targeting niche HCV population with comorbities and resistant to earlier therapies. The objective of the current study is to identify potential anti‐HCV agents from FDA approved drugs that are already in the market for a different disease—Drug repurposing approach. A combination of computational chemistry and computational biology techniques was used to discover potential therapies for hepatitis C targeting the NS5B Thumb I allosteric site. Computational chemistry analysis emphasized the fact that fluvastatin, a lipid lowering agent, and olopatadine, an antihistamine, exhibited good binding affinity to NS5B. In addition, gene set enrichment analysis brought to light the significant overlap between disease characteristic features and the mechanism of action of fluvastatin and olopatadine. The current study concludes the potentially beneficial use of fluvastatin in niche hepatitis C patient population suffering from nonalcoholic fatty liver diseases. The current study focuses on identification of nonstructural protein 5B inhibitors from existing drugs using cheminformatics and conforming the biological activity of hit drugs through genomics analysis.