Theoretical studies of the interaction between influenza virus hemagglutinin and its small molecule ligands.

Hemagglutinin (HA) is a membrane protein present on the influenza viral envelope. It is responsible for molecular recognition between the viral particle and the host cell, as well as fusion of the viral envelope to the endosome bilayer. Because it is essential for influenza viral infection and replication, it has become a target for the design of anti-influenza drugs. Previous studies have identified two small molecule HA ligands (CL-385319 and 1L) that inhibit infection with pseudovirus H5N1 with different potency. In order to compare their different inhibitory activities and shed light on drug design targeting the HA protein, we conducted a variety of theoretical calculations, including docking, molecular dynamics simulations, free energy calculations, as well as quantum calculations to investigate interactions between these two ligands and the HA protein. We found that molecule 1L has stronger π-π interactions with the side chains of residues F110₂ and M24₁ compared with molecule CL-385319. We propose that these stronger π-π interactions are responsible for the higher inhibitory activity of molecule 1L. Our calculations will aid drug design studies targeting the HA protein.