Nesbuvir

To the best of our knowledge, the current study could be considered the first comprehensive one based on the application of molecular docking on the non-nucleoside thumb and palm inhibitors to nonstructural NS5B protein for the detailed evaluation of their binding patterns in the corresponding binding regions in the protein. Non-nucleoside thumb and palm inhibitors were docked into the thumb and palm sites of the nonstructural NS5B protein which is the RNA-dependent RNA polymerase, respectively. Two docking programs, AutoDock 4.2 and AutoDock Vina were employed for the docking of thumb inhibitors (filibuvir and lomibuvir) and palm inhibitors (dasabuvir and nesbuvir) into the respective binding region. The preliminary analysis of the docking performance demonstrated that AutoDock Vina was suitable for the docking of large flexible molecules as deduced from the alignment of docking conformations in all cases. Based on the docking calculation, the interaction pattern analysis was carried out for all the inhibitors which were found to reside in the respective binding region. Before the interaction pattern analysis, the best docking pose was selected based on the high binding affinity value. The interaction pattern analysis of the inhibitors revealed that hydrogen bonding and hydrophobic contacts with amino acid residues of the respective binding region were the leading force in the stabilization of these inhibitors besides other interactions. The interaction pattern analysis based on the docking calculation was also realized to be the meaningful approach to figuring out the relative stability of the protein-ligand complex formed after the inhibitor binding which eventually led to assessing the inhibitory potential of these inhibitors and could also be helpful for the future inhibitor design.

Hepatitis C virus (HCV) NS5B polymerase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Several novel and potent HCV NS5B non-nucleoside inhibitors with unique tetracyclic bezonfuran-based structures were prepared and evaluated. Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species. To better understand the importance of tetracyclic structures related to pan genotypic potency profiles especially against clinically relevant GT1a variants, the teracycles with different ring size were prepared and in vitro evaluations suggested compounds with six number ring have better overall potency profiles.