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Eur J Med Chem. 2019 Apr 5;173:305-313. doi: 10.1016/j.ejmech.2019.04.006. [Epub ahead of print]
Discovery of novel acylhydrazone neuraminidase inhibitors.
Zhao ZX1, Cheng LP2, Li M1, Pang W3, Wu FH4.
Author information
Abstract
Neuraminidase (NA) plays a crucial role in the replication and transmission of influenza virus. NA inhibitors have been developed as effective treatments for influenza A and B infections. In this paper, a new lead neuraminidase inhibitor 6a (IC50 = 7.10 ? 0.2 μM) was discovered by ligand-based virtual screening, receptor-based virtual screening, molecular dynamics simulation (MD), and bioassay validation. MD simulation indicates that the morpholinyl group of 6a could be embedded in 430-loop of NA. To exploit the 430-loop in the active site, a series of novel acylhydrazone NA inhibitors 6b-6g were designed and synthesized based on the lead compound 6a. Compound 6e exerts the most potency, with IC50 value of 2.37 ? 0.5 μM against NA, which is lower than that of oseltamivir carboxylate (OC) (IC50 = 3.84 μM). Overall, this work provided unique insights in the discovery of potent inhibitors against NA.
Copyright ? 2019 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
430-Loop; Acylhydrazone; Neuraminidase inhibitor; Virtual screening
PMID: 31022584 DOI: 10.1016/j.ejmech.2019.04.006
Discovery of novel acylhydrazone neuraminidase inhibitors.
Zhao ZX1, Cheng LP2, Li M1, Pang W3, Wu FH4.
Author information
Abstract
Neuraminidase (NA) plays a crucial role in the replication and transmission of influenza virus. NA inhibitors have been developed as effective treatments for influenza A and B infections. In this paper, a new lead neuraminidase inhibitor 6a (IC50 = 7.10 ? 0.2 μM) was discovered by ligand-based virtual screening, receptor-based virtual screening, molecular dynamics simulation (MD), and bioassay validation. MD simulation indicates that the morpholinyl group of 6a could be embedded in 430-loop of NA. To exploit the 430-loop in the active site, a series of novel acylhydrazone NA inhibitors 6b-6g were designed and synthesized based on the lead compound 6a. Compound 6e exerts the most potency, with IC50 value of 2.37 ? 0.5 μM against NA, which is lower than that of oseltamivir carboxylate (OC) (IC50 = 3.84 μM). Overall, this work provided unique insights in the discovery of potent inhibitors against NA.
Copyright ? 2019 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
430-Loop; Acylhydrazone; Neuraminidase inhibitor; Virtual screening
PMID: 31022584 DOI: 10.1016/j.ejmech.2019.04.006