| Alzheimer’s disease(AD)is a neurodegenerative disease characterized by progressive memory and cognitive deficits.The most recent amyloid ion channel hypothesis,one well accepted theory,holds that destabilization of cellular ionic homeostasis,induced by toxic β-amyloid(Aβ)ion channels/barrels inserting into the membrane,is a pathogenic mechanism for AD.Our previous research by drug screening found a potent anti-AD drug candidate,wgx-50(earlier as gx-50)and a series of experiments were carried out to validate its therapeutic effects on AD.In vivo experiments found that wgx-50 is able to pass through the blood brain barrier and improve the cognitive abilities of mice;in vitro experiments proved that wgx-50 inhibits Aβ-induced neuronal apoptosis and calcium toxicity;molecular dynamics simulations indicated that wgx-50 can disrupt the Aβ protofibril structure.In this work,molecular dynamics simulations are conducted to investigate wgx-50-Aβ channels/barrels interactions,as well as the ion conductance inhibition mechanism.The results showed that ion influx from the extracellular side to the central pore,which is found in simulations without wgx-50,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. |
