Discovery of Potent Sialic Acid Inhibitors Against the Hemagglutinin of Influenza A Virus

Abstract Influenza A virus (IAV) is hard to eradicate due to its genetic drift and reassortment ability. Neuraminidase (NA), frequently the target protein, cleaves the sialic acid (SA) and discharges virions to complete the infectious cycle. However, the increasing use of NA inhibitors aroused drug resistance in recent years. Hemagglutinin (HA), on the opposite, initiates the infectious cycle and sticks virions to cells by connecting to the host SA so that HA might be a tempting target. In this study, HA was chosen for SA-binding site model preparation to screen more than 200,000 compounds by molecular docking method in silico. According to the post-screening analysis by iGemdock and SiMMap, nine of the top twenty compounds based on the ranking score were purchased and evaluated. NSC85561 was initially identified from the compounds through the bioassays. Next, the twelve derivatives of NSC85561 were selected to consolidate the primary results. NSC85561 and two of its derivatives were finally identified as potent HA inhibitors by cell proliferation, plaque reduction, and hemagglutination inhibition assays in vitro. These results suggested that virtual screening may be a powerful tool to concise the compounds from the massive database and reduce the complicated bioassays.