Molecular Dynamics Simulation Study on the Binding and Stabilization Mechanism of Antiprion Compounds to the “Hot Spot” Region of PrPC

Structural transitions in the prion protein from the cellular form, PrPC, into the pathological isoform, PrPSc, are regarded as the main cause of the transmissible spongiform encephalopathies, also known as prion diseases. Hence, discovering and designing effective antiprion drugs that can inhibit PrPC to PrPSc conversion is regarded as a promising way to cure prion disease. Among several strategies to inhibit PrPC to PrPSc conversion, stabilizing the native PrPC via specific binding is believed to be one of the valuable approaches and many antiprion compounds have been reported based on this strategy. However, the detailed mechanism to stabilize the native PrPC is still unknown. As such, to unravel the stabilizing mechanism of these compounds to PrPC is valuable for the further design and discovery of antiprion compounds. In this study, by molecular dynamics simulation method, we investigated the stabilizing mechanism of several antiprion compounds on PrPC that were previously reported to have specific b...