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Hepatitis C, a chronic disease affecting the global population significantly is caused majorly by Hepatitis C virus [HCV]. Among the several druggable targets explored for Hepatitis C, the viral protein, non-structural protein 5B [NS5B] is the target of choice for researchers as it is the key enzyme in the HCV replication and its active site is conserved among all genotypes. In the recent years the landscape of Hepatitis C therapies, have evolved from Peg-Interferon [PEG-INF]/Ribavirin, to directly acting anti-virus along with PEG-INF and finally, INF free regimens with greater than 90% sustained virological response [SVR]. The launch of Sofosbuvir, a nucleotide inhibitor of NS5B marks the major paradigm in hepatitis C research. Sofosbuvir exhibits, pan-genotypic activity, low barrier to resistance, highly effective and safe. However, the high prices of these medications limit their universal access. This review will focus on progress towards the discovery and development of NS5B inhibitors targeting allosteric sites and active site, covering the chemical class and structure-activity relationships.

Objective: The objective of the current study was to elucidate the 3D pharmacophoric features of benzothiadiazine derivatives that are crucial for inhibiting Hepatitis C virus (HCV) Non-structural protein 5B (NS5B) and quantifying the features by building an atom based 3D quantitative structure-activity relationship (3D QSAR) model. Methods:Generation of QSAR model was carried out using PHASE 3.3. Results:A five-point pharmacophore model with two hydrogen bond acceptors, one negative ionization potential and two aromatic rings (AANRR) was found to be common among a maximum number of benzothiadiazine based NS5B inhibitors. A statistically significant 3D QSAR model was obtained from AANRR.6 which had correlation-coefficient (R 2 ) value of 0.924, cross-validated correlation-coefficient (Q 2 ) of 0.774, high Fisher ratio of 138 and low root mean square standard error (RMSE=0.29). There is another parameter, Pearson's R, its value emphasizes correlation between predicted and observed activities of the test set. For the current model, Pearson's R-value is 0.90, hence underlining the good quality of the model. The present study suggests that nitrogen atom of benzothiadiazine sulfamide ring, oxyacetamide group attached to C7 carbon of benzothiadiazine and sulfonamide oxygens are crucial for NS5B inhibitory activity. Prediction of activities of hit drugs generated in earlier research suggests that Aprepitant (Phase predicted activity: 6.9) could be a potential NS5B inhibitor.Conclusion: This 3D QSAR model developed was statistically good and can be used to predict the activities of newly designed NS5B inhibitors and virtual screening as well. Predict the activities of newly designed NS5B inhibitors and virtual screening as well.

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.

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