Abstract
Eradicating influenza A virus (IAV) is difficult, due to its genetic drift and reassortment ability. As the infectious cycle is initiated by the influenza glycoprotein, hemagglutinin (HA), which mediates the binding of virions to terminal sialic acids moieties, HA is a tempting target of anti-influenza inhibitors. However, the complexity of the HA structure has prevented delineation of the structural characterization of the HA protein–ligand complex. Our computational strategy efficiently analyzed > 200,000 records of compounds held in the United States National Cancer Institute (NCI) database and identified potential HA inhibitors, by modeling the sialic acid (SA) receptor binding site (RBS) for the HA structure. Our modeling revealed that compound NSC85561 showed significant antiviral activity against the IAV H1N1 strain with EC50 values ranging from 2.31 to 2.53 µM and negligible cytotoxicity (CC50 > 700 µM). Using the NSC85561 compound as the template to generate 12 derivatives, robust bioassay results revealed the strongest antiviral efficacies with NSC47715 and NSC7223. Virtual screening clearly identified three SA receptor binding site inhibitors that were successfully validated in experimental data. Thus, our computational strategy has identified SA receptor binding site inhibitors against HA that show IAV-associated antiviral activity.
Highlights
Glycosylations in the globular head of the HA is an essential step for viruses to gain virulence and antigenic properties[13]
The structure of the RBS of the HA1 subunit (PDB ID: 1RUY)[25] was selected as the target protein, and 208,023 National Cancer Institute (NCI) compounds were collected as the screening compound database (Fig. 1a)
These 1,000 compounds were re-ranked based on the SiMMap score, and the top 20 compounds were selected as potential candidates
Summary
Glycosylations in the globular head of the HA is an essential step for viruses to gain virulence and antigenic properties[13]. To prevent IAV from obtaining entry to the host cells, the RBS might be a potential target. By interrupting the correct folding of HAs in progeny influenza viruses, HA0 inhibitors elicit nonfunctional HA conformation and block viral e ntry[15]. The HA0 inhibitor AF4H1K1 blocks immature HA0 cleavage and inhibits the infectivity of I AV16. The antiviral mechanism of HA1 inhibitors is mainly attributed to their ability to block receptor binding and prevent the acquisition of a viral infection. Docked compounds were used to recognize interaction preferences by analyzing the RBS with interacting residues and specific physical–chemical properties. These models enabled us to identify inhibitors with novel scaffolds. Our study describes our use of a comprehensive framework for efficient screening of lead compounds for further drug design and development as HA1 inhibitors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
