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

Rao Yu; Li Ping Cheng; Meng Li; Wan Pang

doi:10.1021/acsmedchemlett.9b00447

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

ACS Med Chem Lett. 2019 Nov 25;10(12):1667-1673. doi: 10.1021/acsmedchemlett.9b00447. eCollection 2019 Dec 12.

Authors

Rao Yu¹, Li Ping Cheng¹, Meng Li¹, Wan Pang¹

Affiliation

¹ School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.

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.