Abstract
To discover novel inhibitors that target the influenza polymerase basic protein 2 (PB2) cap-binding domain (CBD), commercial ChemBridge compound libraries containing 384,796 compounds were screened using a cascade docking of LibDock–LigandFit–GOLD, and 60 compounds were selected for testing with cytopathic effect (CPE) inhibition assays and surface plasmon resonance (SPR) assay. Ten compounds were identified to rescue cells from H1N1 virus-mediated death at non-cytotoxic concentrations with EC50 values ranging from 0.30 to 67.65 μM and could bind to the PB2 CBD of H1N1 with Kd values ranging from 0.21 to 6.77 μM. Among these, four compounds (11D4, 12C5, 21A5, and 21B1) showed inhibition of a broad spectrum of influenza virus strains, including oseltamivir-resistant ones, the PR/8-R292K mutant (H1N1, recombinant oseltamivir-resistant strain), the PR/8-I38T mutant (H1N1, recombinant baloxavir-resistant strain), and the influenza B/Lee/40 virus strain. These compounds have novel chemical scaffolds and relatively small molecular weights and are suitable for optimization as lead compounds. Based on sequence and structure comparisons of PB2 CBDs of various influenza virus subtypes, we propose that the Phe323/Gln325, Asn429/Ser431, and Arg355/Gly357 mutations, particularly the Arg355/Gly357 mutation, have a marked impact on the selectivities of PB2 CBD-targeted inhibitors of influenza A and influenza B.
Highlights
Influenza is an acute respiratory infection caused by influenza viruses, including human influenza viruses and animal influenza viruses
During the parameter testing process with GOLD, we found that two key water molecules, HOH 141 and HOH 146, mediated a hydrogen-bonding network between the receptor and VX-787 [26]
From the analysis of the predicted optimal binding modes of these compounds obtained from the docking results, we found that our active molecules bound deep within the PB2 cap-binding domain (CBD), similar to VX-787 and without high strain energy (Figure 3)
Summary
Influenza is an acute respiratory infection caused by influenza viruses, including human influenza viruses and animal influenza viruses. The influenza viruses capable of infecting humans are classified into types A, B, and C based on their core proteins [1]. Influenza A and B viruses are the primary influenza viruses that infect humans and cause seasonal epidemics of disease almost every year. There are 3 to 5 million cases of severe influenza disease worldwide each year, with an estimated. In the 1918–1919 Spanish flu pandemic, at least. 20 to 40 million people worldwide died of the flu [3]. Antiviral drugs are a type of crucial weapon in preventing and treating serious influenza infections, in vulnerable individuals. Three types of approved antiviral drugs have been used:
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