Kinase Inhibitor Intervention on JIIIabc-IRES: A Novel Therapeutic Angle in HCV-Associated HCC

Hepatocellular carcinoma (HCC), commonly linked to chronic Hepatitis C virus (HCV) infection, remains a significant global health challenge. One promising treatment approach involves targeting the internal ribosome entry site (IRES) located in the highly conserved 5[Formula: see text] untranslated region of the HCV genome. The JIIIabc domain of the IRES is particularly important because of its role in recruiting the ribosome and initiating translation. In this study, a drug repurposing strategy was used to identify small-molecule inhibitors that could effectively bind to and stabilize this RNA region. The crystal structure of HCV-IRES (PDB ID: 6U8K) was prepared using UCSF Chimera, and its secondary and tertiary structures were modeled with mfold, trRosettaRNA and RNAComposer. The RNA-binding pocket was identified using DogSite3. A library of 435 clinically trialed kinase inhibitors from the PKIDB database was processed with Open Babel and screened via molecular docking with AutoDock Vina. Rocbrutinib, Fenebrutinib and Bemcentinib emerged as top candidates based on binding affinity. These were further assessed through 500 ns molecular dynamics simulations in GROMACS. Rocbrutinib demonstrated strong and stable interaction with the IRES, maintaining a compact structure and consistent root mean square deviation (RMSD) values, while Bemcentinib showed noticeable instability. Overall, Rocbrutinib exhibited the most favorable binding behavior, indicating its potential as a repurposed therapeutic agent targeting HCV-IRES. These promising results provide a solid foundation for further laboratory studies to evaluate its effectiveness in treating HCV-related HCC.