The hepatitis C virus is a communicable disease that gradually harms the liver leading to cirrhosis and hepatocellular carcinoma. Important therapeutic interventions have been reached since the discovery of the disease. However, its resurgence urges the need for new approaches against this malady. The NS4B receptor is one of the important proteins for Hepatitis C Virus RNA replication that acts by mediating different viral properties. In this work, we opt to explore the relationships between the molecular structures of biologically tested NS4B inhibitors and their corresponding inhibitory activities to assist the design of novel and potent NS4B inhibitors. For that, a set of 115 indol-2-ylpyridine-3-sulfonamides (IPSA) compounds with inhibitory activity against NS4B is used. A hybrid genetic algorithm combined with multiple linear regressions (GA-MLR) was implemented to construct a predictive model. This model was further used and applied to a set of compounds that were generated based on a pharma-cophore modeling study combined with virtual screening to identify structurally similar lead compounds. Multiple filtrations were implemented for selecting potent hits. The selected hits exhibited advantageous molecular features, allowing for favorable inhibitory activity against HCV. The results showed that 7 out of 1285 screened compounds, were selected as potent candidate hits where Zinc14822482 exhibits the best predicted potency and pharmacophore features. The predictive phar-macokinetic analysis further justified the compounds as potential hit molecules, prompting their recommendation for a confirmatory biological evaluation. We believe that our strategy could help in the design and screening of potential inhibitors in drug discovery. ARTICLE HISTORY