Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 10, Issue 12, Pages 1667-1673Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00447
Keywords
Virtual screening; neuraminidase; inhibitors; bioassay
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Funding
- Natural Science Foundation of Shanghai [15ZR1440400]
- Collaborative Innovation Fund [XTCX2016-14]
- Middle and Youth Teachers Scientific and Technological Talents Developing Fund [ZQ 2018-20]
- Shanghai Municipal Education Commission (Plateau Discipline Construction Program)
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Neuraminidase (NA) is a significant therapeutic target for treating influenza. In this study, a new lead NA inhibitor AN-329/10738021 was discovered by structure based virtual screening, molecular dynamics simulations, and bioassay validation. Optimization of lead AN-329/10738021, which holds a novel scaffold of N'-benzylidene benzohydrazone, leads to discovery of some novel NA inhibitors Y-1-Y-11. Compound Y-1 exerts the best inhibition activity (IC50 = 0.21 mu M) against NA, which is better than oseltamivir carboxylate (OSC) (IC50 = 3.04 mu M) and lead AN-329/10738021 (IC50 = 1.92 mu M). Molecular docking analysis indicates that the good potency of Y-1 may be ascribed to the elongation of the benzylidene moiety of the molecule to the 430-cavity. The results of this study may offer useful reference for development of novel NA inhibitors.
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