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.

Docking‐based design and synthesis of galantamine–camphane hybrids as inhibitors of acetylcholinesterase

“…Previous X‐ray structures of the complexes AChE‐GAL derivatives show that both axial and equatorial orientations of the N‐linkers are possible . Recently, it was found that both orientations gave similar docking scores . The protocol was optimized in several steps using two training sets of galantamine derivatives, as described elsewhere .…”

“…[20,24] Recently, it was found that both orientations gave similar docking scores. [36] The protocol was optimized in several steps using two training sets of galantamine derivatives, as described elsewhere. [28,39] At each step, the correlation between the docking scores and the pIC 50 (−logIC 50 ) values of the training compounds was evaluated.…”

“…Several series of GAL derivatives with elongated N-side chains ending with a bulky substituent interacting with PAS have been prepared and tes ted. [19,20,24,26,28,35,36] All of them showed better AChE inhibitory activities than GAL. Camphane (CAM) is a bulky fragment that is unable to bind inside the gorge but disposes well on the wide gorge entrance.…”

“…GAL molecule fits perfectly into AChE binding gorge, but it is short enough to block the PAS. Several series of GAL derivatives with elongated N‐side chains ending with a bulky substituent interacting with PAS have been prepared and tested . All of them showed better AChE inhibitory activities than GAL.…”

Molecular Docking Study on 1-(3-(4-Benzylpiperazin-1-Yl)propyl)-3,7-Dimethyl-1h-Purine-2,6(3h,7h)-Dione as an Acetylcholinesterase Inhibitor

“…The docking simulations were performed by GOLD v. 5.2. (CCDC Ltd., Cambridge, UK) using a protocol previously optimized in terms of scoring function, rigid/flexible ligand and binding site, radius of the binding site, presence/absence of a water molecule (HOH846) within the binding site, number of genetic algorithm (GA) runs (Atanasova et al, 2015a, Atanasova et al, 2015b, Stavrakov et al, 2016, Stavrakov et al, 2017. The docking simulations in the present study were performed at the following settings: scoring function ChemPLP, flexible ligand, rigid protein, radius of the binding site 6Å, no water molecule, 100 GA runs.…”