%0 Journal Article %A Tran-Nguyen, V.K. %A Le, M.T. %A Tran, T.D. %A Truong, V.D. %A Thai, K.M. %D 2019 %T Peramivir binding affinity with influenza A neuraminidase and research on its mutations using an induced-fit docking approach %U https://tandf.figshare.com/articles/journal_contribution/Peramivir_binding_affinity_with_influenza_A_neuraminidase_and_research_on_its_mutations_using_an_induced-fit_docking_approach/10033091 %R 10.6084/m9.figshare.10033091.v1 %2 https://tandf.figshare.com/ndownloader/files/18090281 %K Influenza A virus %K neuraminidase %K inhibitor %K peramivir %K in silico mutation %K induced-fit docking %K binding affinity %X

Influenza A virus (IAV) has caused epidemic infections worldwide, with many strains resistant to inhibitors of a surface protein, neuraminidase (NA), due to point mutations on its structure. A novel NA inhibitor named peramivir was recently approved, but no exhaustive computational research regarding its binding affinity with wild-type and mutant NA has been conducted. In this study, a thorough investigation of IAV-NA PDB entries of 9 subtypes is described, providing a list of residues constituting the protein-ligand binding sites. The results of induced-fit docking approach point out key residues of wild-type NA participating in hydrogen bonds and/or ionic interactions with peramivir, among which Arg 368 is responsible for a peramivir-NA ionic interaction. Mutations on this residue greatly reduced the binding affinity of peramivir with NA, with 3 mutations R378Q, R378K and R378L (NA6) capable of deteriorating the docking performance of peramivir by over 50%. 200 compounds from 6-scaffolds were docked into these 3 mutant versions, revealing 18 compounds giving the most promising results. Among them, CMC-2012-7-1527-56 (benzoic acid scaffold, IC50 = 32 nM in inhibitory assays with IAV) is deemed the most potential inhibitor of mutant NA resisting both peramivir and zanamivir, and should be further investigated.

%I Taylor & Francis