Virtual screening, optimization design, and synthesis analysis of novel benzofuran derivatives as pan-genotypic HCV NS5B polymerase inhibitors using molecular modeling.

Abstract

Hepatitis C virus (HCV) infection is a global health concern, with HCV exhibiting high variability across eight major genotypes and multiple subtypes. A series of benzofuran inhibitors have been proven to exhibit effective antiviral effects on HCV NS5B polymerase of multiple genotypes. Given the pan-genotypic inhibitory potential exhibited by such inhibitors, this study concentrates on the development of novel and effective pan-genotypic inhibitors against HCV NS5B polymerase. Through conducting virtual screening based on molecular structure similarity and docking, potential lead compounds ZINC103262402, ZINC215816615, and ZINC215876403 were identified. Molecular dynamics simulations and binding free energy calculations indicated that these compounds can stably bind to HCV NS5B polymerases of various genotypes. ADMET prediction revealed that ZINC215816615 and ZINC215876403 possess superior pharmacokinetic profiles. Further investigation into the binding mode of the benzofuran analogs with NS5B polymerase facilitated the design of new molecules, BFD-01 and BFD-02, through fragment growth. The groups of BFD-01 and BFD-02 extended on the basis of retaining the structure of the lead compound, enhancing hydrophobicity, and forming new hydrogen bonds to improve the binding ability. This research provides valuable insights for the development of novel pan-genotypic HCV NS5B polymerase inhibitors.