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.

Novel hits for acetylcholinesterase inhibition derived by docking-based screening on ZINC database

“…GAL easily crosses the intestinal mucosa ( pPe GIT =5.060) which corresponds well to its oral bioavailability of 90% 52 . The value of 5.060 for pPe BBB, found in our previous study 39 , indicates for moderate ability to cross the BBB by passive diffusion but mediation by choline transport system has been suggested 55 . GAL binds mainly in CAS; only the methoxy group interacts with Phe295, Phe297 and Phe338 from PAS.…”

“…The − log Pe for the rest compounds ranges from 4.146 to 4.731 for the BBB permeability and from 4.202 to 4.469 for the GIT permeability at pH = 6.2. For comparison, GAL has − log Pe 5.060 and 4.268 for BBB and GIT permeability, respectively 39 , which corresponds well to its low ability to penetrate BBB by passive diffusion 51 and to 90% oral bioavailability 52 . Moderate correlations exist between log D 7.4 and BBB permeability ( r = 0.693) and between log D 7.4 and GIT permeability ( r = 0.637) of the tested compounds.…”

“…AChE from electric eel ( ee AChE) was used in the measurements. The UniProt alignment of rh AChE (UniProt: P22303) and еe AChЕ (UniProt: O42275) have showed that all 17 residues forming the binding gorges are identical 39 . Our previous experience has shown that the docking scores predicted for rh AChE correlate well with the experimental binding affinity measured on ee AChE 36–39 .…”

Iridoids and Other Monoterpenes in the Alzheimer’s Brain: Recent Development and Future Prospects

“…The vast arrays of neuroprotective effects of iridoids and some monoterpenes are shown in Table 1 [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. The Aβ formation, aggregation and function have been the major target areas of AD for in vitro experiments.…”

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.…”