Authors: Rollinger, J. M.; Mock, P.; Zidorn, C.; Ellmerer, E. P.; Langer, T.; Stuppner, H.

Source: Current Drug Discovery Technologies, Volume 2, Number 3, September 2005 , pp. 185-193(9)

Publisher: Bentham Science Publishers

Abstract:

Because of the direct correlation of cholinergic deficit and the severity of dementia, Alzheimer's disease is preferentially treated with acetylcholinesterase (AChE) inhibitors to supplement the acetylcholine level. In this study we focused on non-alkaloid AChE inhibitors from natural sources in order to discover new lead structures.

In the course of in vitro extract screening of Tyrolean plants using an enzyme assay with Ellman's reagent, the dichloromethane extract of chicory roots (Cichorium intybus L.) showed a pronounced inhibitory effect on AChE. At a concentration of 1 mg extract/ml an inhibition of 70% was measured. Based on a 3D multi-conformational molecularstructure database consisting of secondary metabolites from C. intybus known from the relevant literature, virtual screening filtering experiments were conducted using both a feature-based pharmacophore model and a docking procedure. Some low molecular weight sesquiterpenoids exhibited distinct interactions with the pharmacophore model.

In order to verify the applicability of this computer-aided strategy, an activity-guided fractionation of the chicory root extract was performed, which resulted in the isolation of two sesquiterpene lactones, 8-deoxylactucin and lactucopicrin, showing significant and dose-dependent inhibitory activity on AChE (IC50 of 308.1 M [CI95 243.9 - 405.3 M] and 150.3 M [CI95 100.8 - 188.1 M], respectively). The two isolates were correctly predicted within the virtual screening process which corroborates the potential of the computer-assisted in combo screening approach for the discovery of the anti-cholinesterase compounds from C. intybus.

Keywords: in combo screening; chicory root; sesquiterpene lactones; activity-guided fractionation; virtual screening; pharmacophore model; acetylcholinesterase; alzheimers disease

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1570163054866855

Affiliations: 1: Institute of Pharmacy / Pharmacognosy, Josef-Moeller-Haus, Innrain 52c, Leopold-Franzens- University Innsbruck, 6020 Innsbruck, Austria.

Publication date: 2005-09-01

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• Due to the plethora of new approaches being used in modern drug discovery by the pharmaceutical industry, Current Drug Discovery Technologies has been established to provide comprehensive overviews of all the major modern techniques and technologies used in drug design and discovery. The journal is the forum for publishing both original research papers and reviews describing novel approaches and cutting edge technologies used in all stages of drug discovery. The journal addresses the multidimensional challenges of drug discovery science including integration issues of the drug discovery process.
  
  Current Drug Discovery Technologies is an essential journal for all scientists and research managers involved in drug discovery who wish to keep abreast of all the modern techniques and technologies used in drug discovery.

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