Structure-based design and in silico evaluation of 1-benzyl-1h-1,2,4-triazole derivatives as potential inhibitors of hepatitis c virus NS5B polymerase

Hepatitis C virus (HCV) infection remains a global health burden, affecting nearly 58 million people worldwide. The NS5B polymerase, an RNA-dependent RNA polymerase essential for viral replication, is a validated therapeutic target due to the absence of a human homolog. Despite direct-acting antivirals (DAAs), challenges such as high costs, limited accessibility, and emerging resistance necessitate novel agents. In this study, six novel 1-benzyl-1H-1,2,4-triazole derivatives were designed and computationally evaluated for NS5B polymerase inhibition using AutoDock Vina. The docking protocol was validated with an RMSD of 1.326 Å, confirming reliability. All derivatives exhibited favorable binding affinities, with halogenated compounds (1a and 1b) demonstrating enhanced hydrogen bonding, hydrophobic contacts, and π–π stacking with key residues including Ser556, Arg386, Tyr448, and Phe193. Lipinski's Rule of Five assessment revealed zero violations for all compounds, with molecular weights (159.19 – 204.19 Da) and LogP values (1.33 – 2.68) indicating favorable oral bioavailability. In silico ADME profiling using SwissADME showed high human intestinal absorption (97.36 – 98.40 %), absence of P-glycoprotein substrate activity, and no CYP3A4 inhibition, suggesting low risk of drug–drug interactions. All compounds satisfied Veber's criteria, with TPSA values of 30.71 – 33.73 Ų and two rotatable bonds, confirming excellent membrane permeability. Synthetic accessibility scores of 1.48 indicated ready synthesizability. Compounds 1a and 1b emerged as promising leads, combining strong binding affinity with optimal pharmacokinetic profiles. These findings demonstrate that the designed triazole derivatives possess favorable structural and pharmacokinetic properties for NS5B polymerase inhibition, warranting further experimental validation as novel anti-HCV agents.