Publication Type:

Journal Article


Bioorganic and Medicinal Chemistry, Volume 20, Number 22, p.6669-6679 (2012)



acetylcholinesterase, amyloid beta protein, Amyloid beta-Peptides, article, Benzophenanthridines, berberine, Binding Sites, Butyrylcholinesterase, Catalytic Domain, catharanthine, chelerythrine, cholinesterase, cholinesterase inhibition, Cholinesterase Inhibitors, deoxyvasicine, drug identification, drug mechanism, drug potency, drug protein binding, drug screening, drug selectivity, drug targeting, E6 berbamine, enzyme active site, himbacine, hirsutine, Humans, IC 50, Isoquinolines, kinetics, molecular docking, Molecular Docking Simulation, natural product, nitrarine, oxyacanthine sulfate, palmatine, peganole, propidium iodide, protein aggregation, quinidine, rauwolscine, sevedindione, Structure-Activity Relationship, unclassified drug, vasicine, veratramine


The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin - chelerythrine - acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs. © 2012 Elsevier Ltd. All rights reserved.


cited By (since 1996)5

Cite this Research Publication

Ga Brunhofer, Fallarero, Aa, Karlsson, Da, Batista-Gonzalez, Aa, Shinde, Pb, Mohan, CbGopi, and Vuorela, Pa, “Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: The case of chelerythrine”, Bioorganic and Medicinal Chemistry, vol. 20, pp. 6669-6679, 2012.