Discovery of Novel Neuraminidase Inhibitors by Structure-Based Virtual Screening, Structural Optimization, and Bioassay.
Yu R, Cheng LP, Li M, Pang W.
Neuraminidase (NA) is a significant therapeutic target for treating influenza. In this study, a new lead NA inhibitor <b>AN-329/10738021</b> was discovered by structure-based virtual screening, molecular dynamics simulations, and bioassay validation. Optimization of lead <b>AN-329/10738021</b>, which holds a novel scaffold of <i>N</i>'-benzylidene benzohydrazone, leads to discovery of some novel NA inhibitors <b>Y-1</b>-<b>Y-11</b>. Compound <b>Y-1</b> exerts the best inhibition activity (IC<sub>50</sub> = 0.21 μM) against NA, which is better than oseltamivir carboxylate (OSC) (IC<sub>50</sub> = 3.04 μM) and lead <b>AN-329/10738021</b> (IC<sub>50</sub> = 1.92 μM). Molecular docking analysis indicates that the good potency of <b>Y-1</b> 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.