Towards the characterization of DAPT interaction with γ-secretase.

In this study, we employed the density map data to assign a possible binding pose of DAPT to characterize its dynamic behaviour through different molecular dynamics simulation approaches. Our simulations showed a high preference of DAPT for the intramembrane region of the protein and also that its entry site is located between TM2 and TM3 of PS1. DAPT interaction with the active site led to a decrease flexibility of key PS1 regions related to the recognition and internalization of GS substrates. Moreover, our study showed that the proximity of DAPT to the catalytic aspartic acids should be able to modify its protonation states, preventing the enzyme from reaching its active form. These results provide valuable information towards understanding the molecular mechanism of a GS inhibitor for the development of novel Alzheimer's disease treatments.
PMID: 30925201 [PubMed - as supplied by publisher]

Source: ChemMedChem - March 28, 2019 Category: Chemistry Authors: Aguayo-Ortiz R, Guzmán-Ocampo DC, Dominguez L Tags: ChemMedChem Source Type: research