In Silico Binding Mode Proposed for Flavonoid Ligands of Tau Protein with Interest in Alzheimer's Disease

An intracellular hallmark of Alzheimer's Disease (AD) is accumulation of hyperphosphorylated tau as paired helical filaments (PHF). A significant advance in understanding the behavior of tau occurred when it was reported that VQIVYK hexapeptide motif is responsible for initiating the process of aggregation. In the last years, a great number of Tau aggregation inhibitors have been developed, including flavonoids. However, the binding mode of these potential drugs is not well established. In this work, the behavior and conformational stability of the Tau hexapeptide306VQIVYK311 were investigated in the presence of two known flavonoid inhibitors using Molecular Interaction Fields (MIFs), pharmacophore perception and molecular dynamics (MD) simulations. We have also proposed a likely binding mode for such inhibitors with the hexapeptide, which agrees with experimental data and is able to explain structure-activity relationships between different flavonoids.