Peramivir binding affinity with influenza A neuraminidase and research on its mutations using an induced-fit docking approach

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 regardin...

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Bibliographic Details
Published in:SAR and QSAR in environmental research 2019-12, Vol.30 (12), p.899-917
Main Authors: Tran-Nguyen, V.K., Le, M.T., Tran, T.D., Truong, V.D., Thai, K.M.
Format: Article
Language:English
Subjects:
Affinity
Antiviral Agents - chemistry
Benzoic acid
binding affinity
Binding Sites
Chemical Sciences
Computer applications
Cyclopentanes - chemistry
Enzyme Inhibitors - chemistry
Epidemics
Exo-a-sialidase
Guanidines - chemistry
Hydrogen bonding
Hydrogen bonds
in silico mutation
induced-fit docking
Influenza
Influenza A virus
inhibitor
Inhibitors
Inhibitory Concentration 50
Ionic interactions
Molecular Docking Simulation
Mutation
neuraminidase
Neuraminidase - antagonists & inhibitors
Neuraminidase - chemistry
Neuraminidase - genetics
peramivir
Proteins
Quantitative Structure-Activity Relationship
Residues
Scaffolds
Viral Proteins - antagonists & inhibitors
Viral Proteins - chemistry
Viral Proteins - genetics
Viruses
Zanamivir
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Summary: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.
ISSN:1062-936X
1029-046X
DOI:10.1080/1062936X.2019.1679248