tetano
Editor, Senior Moderator
SAR QSAR Environ Res. 2019 Oct 24:1-19. doi: 10.1080/1062936X.2019.1679248. [Epub ahead of print] [h=1]Peramivir binding affinity with influenza A neuraminidase and research on its mutations using an induced-fit docking approach.[/h]
Tran-Nguyen VK[SUP]1[/SUP], Le MT[SUP]1,[/SUP][SUP]2[/SUP], Tran TD[SUP]1[/SUP], Truong VD[SUP]1[/SUP], Thai KM[SUP]1[/SUP].
[h=3]Author information[/h] 1 Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City , Ho Chi Minh City , Vietnam. 2 School of Medicine, Vietnam National University Ho Chi Minh City , Ho Chi Minh City , Vietnam.
[h=3]Abstract[/h] 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.
[h=4]KEYWORDS:[/h] Influenza A virus; binding affinity; in silico mutation; induced-fit docking; inhibitor; neuraminidase; peramivir
PMID: 31645133 DOI: 10.1080/1062936X.2019.1679248
Tran-Nguyen VK[SUP]1[/SUP], Le MT[SUP]1,[/SUP][SUP]2[/SUP], Tran TD[SUP]1[/SUP], Truong VD[SUP]1[/SUP], Thai KM[SUP]1[/SUP].
[h=3]Author information[/h] 1 Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City , Ho Chi Minh City , Vietnam. 2 School of Medicine, Vietnam National University Ho Chi Minh City , Ho Chi Minh City , Vietnam.
[h=3]Abstract[/h] 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.
[h=4]KEYWORDS:[/h] Influenza A virus; binding affinity; in silico mutation; induced-fit docking; inhibitor; neuraminidase; peramivir
PMID: 31645133 DOI: 10.1080/1062936X.2019.1679248