Acetylcholinesterase Inhibitors with PhotoswitchableInhibition of β-Amyloid Aggregation

摘要

Photochromic cholinesterase inhibitors were obtained from cis-1,2-α-dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target compounds are potent acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors in the nanomolar concentration range. Compound >11b bearing an octylene linker exhibited interactions with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Yet upon irradiation with light, the mechanism of interaction varied from one photochromic form to another, which was investigated by kinetic studies and proved “photoswitchable”. The AChE-induced β-amyloid (Aβ) aggregation assay gave further experimental support to this finding: Aβ1–40 aggregation catalyzed by the PAS of AChE might be inhibited by compound >11b in a concentration-dependent manner and seems to occur only with one photochromic form. Computational docking studies provided potential binding modes of the compound. Docking studies and molecular dynamics (MD) simulations for the ring-open and -closed form indicatea difference in binding. Although both forms can interact with thePAS, more stable interactions are observed for the ring-open formbased upon stabilization of a water molecule network within the enzyme,whereas the ring-closed form lacks the required conformational flexibilityfor an analogous binding mode. The photoswitchable inhibitor identifiedmight serve as valuable molecular tool to investigate the differentbiological properties of AChE as well as its role in pathogenesisof AD in in vitro assays.