Inhibition of β‑Amyloid Channels with a Drug Candidate wgx-50 Revealed by Molecular Dynamics Simulations

Destabilization of cellular ionic homeostasis by toxic β-amyloid (Aβ) channels/barrels, which is a pathogenic mechanism for Alzheimer’s disease (AD), is inhibited by a novel anti-AD drug candidate wgx-50 significantly in our previous biological experiments. In this work, molecular dynamics simulations are conducted to investigate wgx-50–Aβ channels/barrels interactions, as well as the ion conductance inhibition mechanism. Ion influx from the extracellular side to the central pore, which is found in apo-form simulations, is blocked by wgx-50 ligands that bind to the hydrophobic rings at the entrance of the channels/barrels. The wgx-50 binding results in smaller pore diameter of the channels/barrels; however, the overall morphology of them remains unaffected in accessible simulation time. The wgx-50 binding site in this work is consistent with what we found in our previous simulations of Aβ protofibril. Our work not only investigates the ligand-Aβ channels/barrels interaction mechanism but also provides insights into the rational drug design of Alzheimer’s disease.