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 Abeta 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 Abeta aggregation as well as the ability to disaggregate already preformed Abeta aggregates in an experimental set-up using HFIP as promotor of Abeta 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 Abeta 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 Abeta aggregation as well as to disaggregate preformed Abeta aggregates This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
