Molecular basis of benzimidazole inhibitors to hepatitis C virus envelope glycoprotein.

The molecular basis for the inhibitory action of a benzimidazole inhibitor compound to hepatitis C virus E1 envelope protein was examined computationally. Structures for the wild-type E1 protein and seven mutants were modelled using an ab initio protein structure prediction algorithm, and these models were docked with the benzimidazole inhibitor. Top-ranked conformers for each docked structure were examined in the context of the putative function of the inhibitor that blocks fusion of the envelope protein to the host cells. The results for the wild-type protein and that for a series of mutants containing reported single, double and triple resistance mutations demonstrate that the inhibitor binds in the vicinity of residue Phe99 (at position 291 in the encoded polyprotein) at the C-terminal end of a putative fusion domain. In so doing, the compound inhibits the virus from fusing to host cells and blocks viral replication in accord with the results from cell-based infection studies.