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

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.

Discovery of hit molecules targeting allosteric site of hepatitis C virus NS5B polymerase.

Nonstructural protein 5B (NS5B), the RNA-dependent RNA polymerase of Hepatitis C Virus (HCV), plays a key role in viral amplification and is an attractive and most explored target for discovery of new therapeutic agents for Hepatitis C. Though safe and effective, NS5B inhibitors were launched in 2013 (Sovaldi) and 2014 (Harvoni, Viekira Pak), the high price tags of these medications limit their use among poor people in developing countries. Hence, still there exists a need for cost-effective and short duration anti-HCV agents especially those targeting niche patient population who were non-respondent to earlier therapies or with comorbid conditions. The present study describes the discovery of novel non-nucleoside (NNI) inhibitors of NS5B using a series of rational drug design techniques such as virtual screening, scaffold matching and molecular docking. 2D and 3D structure based virtual screening technique identified 300 hit compounds. Top 20 hits were screened out from identified hits using molecular docking technique. Four molecules, that are representative of 20 hits were evaluated for binding affinity under in vitro conditions using surface plasmon resonance-based assay and the results emphasized that compound with CoCoCo ID: 412075 could exhibit good binding response toward NS5B and could be a potential candidate as NS5B inhibitor.Communicated by Ramaswamy H. Sarma.

The drug repurposing landscape from 2012 to 2017: evolution, challenges, and possible solutions.

As the name suggests, drug repurposing is a strategy to identify new therapeutic uses for marketed drugs, discontinued and/or shelved drugs, and drug candidates currently in clinical development. Although not a recent concept, drug repurposing has gained momentum over the past few years and several drugs have been successfully repurposed. Here, we summarize the drug repurposing landscape from 2012 to 2017, with a major focus on repurposed drugs, collaborative opportunities, and funding opportunities specific to drug repurposing projects. Along with success stories, we also highlight the challenges and limitations associated with drug repurposing.