title: Docking-based design and synthesis of galantamine-camphane hybrids as inhibitors of acetylcholinesterase.
abstract: Galantamine (GAL) as an acetylcholinesterase inhibitor (AChEI) is among the main drugs approved for the treatment of Alzheimer's disease. It fits perfectly into acetylcholinesterase (AChE) binding gorge, but it is too short to fill it. The amyloid beta (Aβ) peptide binds in the peripheral anionic site (PAS) at the entrance of the binding gorge of AChE and initiates the formation of amyloid plaques. The blockade of PAS prevents from AChE-induced Aβ aggregation. In this study, we describe the design of a series of galantamine-camphane hybrids as AChEIs. Camphane (CAM) is a bulky fragment that disposes well on the wide gorge entrance. The designed hybrids have linkers of different length. They were docked into AChE, and the highest scored compounds were synthesized and tested for AChE inhibitory activity. Some of the novel hybrids showed 191- and 369-fold better inhibition than GAL. The CAM fragment of the best binders fits in the same region, proximal to PAS, where the Ω-loop of Aβ binds to AChE. The hybrids cross blood-brain barrier by passive diffusion and are non-neurotoxic at the inhibitory concentrations.
authors.affiliation: Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria.
authors.forename: Georgi
authors.initials: G
authors.lastname: Stavrakov
authors.affiliation: Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Irena
authors.initials: I
authors.lastname: Philipova
authors.affiliation: Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria.
authors.forename: Dimitrina
authors.initials: D
authors.lastname: Zheleva-Dimitrova
authors.affiliation: Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria.
authors.forename: Iva
authors.initials: I
authors.lastname: Valkova
authors.affiliation: Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Evdokiya
authors.initials: E
authors.lastname: Salamanova
authors.affiliation: Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria.
authors.forename: Spiro
authors.initials: S
authors.lastname: Konstantinov
authors.affiliation: Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria.
authors.forename: Irini
authors.identifier: http://orcid.org/0000-0002-1469-1768
authors.initials: I
authors.lastname: Doytchinova
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001892:Camphanes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004593:Electrophorus; D005702:Galantamine / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation
chemical_list: D001892:Camphanes; D002800:Cholinesterase Inhibitors; D005702:Galantamine; C067796:camphane; D000110:Acetylcholinesterase
keywords: BBB permeability; ChemPLP; acetylcholinesterase inhibitors; amyloid beta peptide; camphane; dual-site binding; galantamine; molecular docking