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

Journal of Chemical Information and Modeling
Shuang HouDong-Qing Wei

Abstract

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.

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Citations

Mar 20, 2020·International Journal of Molecular Sciences·Stefano MuscatMarco Agostino Deriu
Feb 4, 2021·ACS Chemical Neuroscience·Yehong GongQingwen Zhang
Dec 25, 2019·Journal of Chemical Information and Modeling·Neeraj KumarRamesh Chandra
May 23, 2020·ACS Chemical Neuroscience·Chendi ZhanGuanghong Wei

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