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Docking‐based Design of Galantamine Derivatives with Dual‐site Binding to Acetylcholinesterase
Author(s) -
Stavrakov Georgi,
Philipova Irena,
Zheleva Dimitrina,
Atanasova Mariyana,
Konstantinov Spiro,
Doytchinova Irini
Publication year - 2016
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201600041
Subject(s) - galantamine , acetylcholinesterase , moiety , chemistry , docking (animal) , stereochemistry , binding site , active site , substituent , rational design , combinatorial chemistry , enzyme , biochemistry , donepezil , nanotechnology , medicine , dementia , materials science , nursing , disease , pathology
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.