title: Docking-based Design of Galantamine Derivatives with Dual-site Binding to Acetylcholinesterase.
abstract: The enzyme acetylcholinesterase is a key target in the treatment of Alzheimer's disease because of its ability to hydrolyze acetylcholine via the catalytic binding site and to accelerate the aggregation of amyloid-β peptide via the peripheral anionic site (PAS). Using docking-based predictions, in the present study we design 20 novel galantamine derivatives with alkylamide spacers of different length ending with aromatic fragments. The galantamine moiety blocks the catalytic site, while the terminal aromatic fragments bind in PAS. The best predicted compounds are synthesized and tested for acetylcholinesterase inhibitory activity. The experimental results confirm the predictions and show that the heptylamide spacer is of optimal length to bridge the galantamine moiety bound in the catalytic site and the aromatic fragments interacting with PAS. Among the tested terminal aromatic fragments, the phenethyl substituent is the most suitable for binding in PAS.
authors: Faculty of Pharmacy, Medical University of Sofia, 2 Dunav str., 1000, Sofia, Bulgaria.
authors: Georgi
authors: G
authors: Stavrakov
authors: Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian academy of Sciences, Acad. G. Bonchev str. 9, 1113, Sofia, Bulgaria.
authors: Irena
authors: I
authors: Philipova
authors: Faculty of Pharmacy, Medical University of Sofia, 2 Dunav str., 1000, Sofia, Bulgaria.
authors: Dimitrina
authors: D
authors: Zheleva
authors: Faculty of Pharmacy, Medical University of Sofia, 2 Dunav str., 1000, Sofia, Bulgaria.
authors: Mariyana
authors: M
authors: Atanasova
authors: Faculty of Pharmacy, Medical University of Sofia, 2 Dunav str., 1000, Sofia, Bulgaria.
authors: Spiro
authors: S
authors: Konstantinov
authors: Faculty of Pharmacy, Medical University of Sofia, 2 Dunav str., 1000, Sofia, Bulgaria. idoytchinova@pharmfac.net.
authors: Irini
authors: I
authors: Doytchinova
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D015195:Drug Design; D005702:Galantamine / Q000031:analogs & derivatives* / Q000737:chemistry*; D008958:Models, Molecular; D062105:Molecular Docking Simulation
chemical_list: D002800:Cholinesterase Inhibitors; D005702:Galantamine; D000110:Acetylcholinesterase
keywords: ChemPLP; acetylcholinesterase inhibitors; amyloid beta peptide; dual-site binding; galantamine; molecular docking