title: Acetylcholinesterase inhibitors with photoswitchable inhibition of β-amyloid aggregation.
abstract: 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 indicate a difference in binding. Although both forms can interact with the PAS, more stable interactions are observed for the ring-open form based upon stabilization of a water molecule network within the enzyme, whereas the ring-closed form lacks the required conformational flexibility for an analogous binding mode. The photoswitchable inhibitor identified might serve as valuable molecular tool to investigate the different biological properties of AChE as well as its role in pathogenesis of AD in in vitro assays.
authors.affiliation: Institut für Pharmazie, ‡Institut für Organische Chemie, Universität Regensburg , Universitätsstraße 31, 93053 Regensburg, Germany.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Chen
authors.forename: Sarah
authors.initials: S
authors.lastname: Wehle
authors.forename: Natascha
authors.initials: N
authors.lastname: Kuzmanovic
authors.forename: Benjamin
authors.initials: B
authors.lastname: Merget
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Burkhard
authors.initials: B
authors.lastname: König
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Sotriffer
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D017319:Photosensitizing Agents / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D017319:Photosensitizing Agents; D066329:Protein Aggregates