Discovery of Novel Neuraminidase Inhibitors by Structure-Based Virtual Screening, Structural Optimization, and Bioassay.

ABSTRACT

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 µM) against NA, which is better than oseltamivir carboxylate (OSC) (IC50 = 3.04 µM) and lead AN-329/10738021 (IC50 = 1.92 µM). 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.