Abstract
Influenza viruses are a major public health threat worldwide. The influenza hemagglutinin (HA) plays an essential role in the virus life cycle. Due to the high conservation of the HA stem region, it has become an especially attractive target for inhibitors for therapeutics. In this study, molecular simulation was applied to study the mechanism of a small molecule inhibitor (MBX2329) of influenza HA. Behaviors of the small molecule under neutral and acidic conditions were investigated, and an interesting dynamic binding mechanism was found. The results suggested that the binding of the inhibitor with HA under neutral conditions facilitates only its intake, while it interacts with HA under acidic conditions using a different mechanism at a new binding site. After a series of experiments, we believe that binding of the inhibitor can prevent the release of HA1 from HA2, further maintaining the rigidity of the HA2 loop and stabilizing the distance between the long helix and short helices. The investigated residues in the new binding site show high conservation, implying that the new binding pocket has the potential to be an effective drug target. The results of this study will provide a theoretical basis for the mechanism of new influenza virus inhibitors.
Highlights
Influenza virus is the causative agent of influenza, an infectious disease which usually leads to symptoms such as high fever, cough, headache, muscle and joint pain, sore throat, nasal discharge, and even a fatal illness similar to pneumonia[1,2,3,4]
In order to explore molecular inhibition mechanism of new HA inhibitors, in this study, molecular docking, molecular dynamics simulation and the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) approach were applied to study the detailed mechanism of HA inhibition of this representative compound MBX2329, which hereafter is referred to as INT for convenience[16]
After entering into the endosome, HA will undergo large conformational changes under acidic conditions, which is aimed at promoting the membrane fusion between the virus and host cell[1, 3]
Summary
Acidic condition structure)[3, 14, 15]. The N-terminal segment next to the short helix is a fusion peptide consisting of 20 amino acids, while the C-terminal end of the long helix is anchored to the viral membrane[3]. Acidic pH conditions in the endosome can trigger conformational changes involving a folding of the loop connecting the two helices of HA2 into a new longer helix (coiled-coil structure) of the HA ectodomain (loop-to-helix transition) and further trigger its membrane fusion capacity[1, 3]. Other HA-inhibiting compounds such as BMY 2770918, 180299 (podocarpic acid derivative)[19] and tert-butyl hydroquinone (TBHQ)[20] have been confirmed. These compounds can serve as starting points for the development of a therapeutic agent. The findings of this study will be useful for future exploration of efficient drug targets and provide theoretical insight into a new mechanism of influenza virus inhibitors
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