Computational Exploration of Flavonoids as HCV NS3/4A Protease Inhibitors: Advancing Antiviral Therapies to Mitigate Liver Cancer Risk.

[INTRODUCTION] Hepatitis C virus (HCV) remains a major global health challenge, driving chronic hepatitis C (CHC) progression to severe liver diseases, including hepatocellular carcinoma (HCC). Directacting antivirals (DAAs) have transformed HCV treatment by achieving high sustained virological response (SVR) rates. However, limitations such as resistance, reinfection, and restricted accessibility emphasize the urgent need for novel therapeutic approaches. Among HCV therapeutic targets, the NS3/4A protease is critical for viral replication and immune evasion, positioning it as a prime focus for innovative drug discovery.

[METHODS] A comprehensive computational approach was adopted to evaluate flavonoids, natural compounds with known antiviral and anticancer properties, as potential inhibitors of the HCV NS3/4A protease. A curated flavonoid library was subjected to virtual screening using molecular docking techniques. Top-ranked flavonoids were further assessed based on binding affinity, dissociation constants, and key protein-ligand interactions. Pharmacokinetic profiling, molecular dynamics simulations, MM/PBSA energy calculations, and principal component analysis were performed to validate the most promising candidate.

[RESULTS] The top ten scoring flavonoids demonstrated strong binding affinities and stable interactions with key catalytic residues of the NS3/4A protease. CID 100943380 emerged as the most promising candidate, exhibiting favorable pharmacokinetic properties and sustained stability throughout molecular dynamics simulations. MM/PBSA and PCA analyses further confirmed its robust binding and conformational stability.

[DISCUSSION] The findings highlight flavonoids as promising inhibitors of NS3/4A protease, supporting their potential for further antiviral development.

[CONCLUSION] This investigation identifies 10 flavonoids with high potential as NS3/4A protease inhibitors, providing a basis for future biological validation and safer drug development.