Identification of Novel Neuraminidase Inhibitors as Potential Anti-Influenza Agents: Virtual Screening, Molecular Docking, in vitro Validation and Molecular Dynamic Simulation Studies.

The influenza virus causes approximately hundreds of thousands of deaths annually. Coupled with the emergence of drug resistance, there is an urgent need to develop new drugs for the treatment of influenza. Neuraminidase (NA) has long been recognized as a valid drug target for anti-influenza therapy. Herein, in order to identify potential NA inhibitors with novel structures, we employed a structure-based virtual screening strategy to screen a library containing 1.6 million compounds. Based on XP docking score and free energy calculation results, the three compounds E570-1769, K788-4718, and C071-0424 were selected that may have better binding affinity for the NA protein compared to oseltamivir. Amongst, E570-1769 was identified to be the most potential hit. Docking study showed that E570-1769 bound to NA with a binding energy of -10.3 kcal/mol. Moreover, in silico ADME/T studies demonstrated the druggability of E570-1769 was quite well. Furthermore, in vitro assay demonstrated that E570-1769 inhibited the wild-type and H274Y-muatated NAs with IC values of 72.6 μM and 229 μM, respectively. Additionally, molecular dynamic (MD) simulation studies were performed to gain a deep insight into the binding modes of E570-1769 in complex with NA. While less potent than oseltamivir, the novel structure of E570-1769 and promising ADME/T properties indicates it as a promising lead for future research.