Taspine: bioactivity-guided isolation and molecular ligand-target insight of a potent acetylcholinesterase inhibitor from Magnolia x soulangiana.
A bioactivity-guided approach was taken to identify the acetylcholinesterase (AChE, EC 3.1.1.7) inhibitory agent in a Magnolia x soulangiana extract using a microplate enzyme assay with Ellman's reagent. This permitted the isolation of the alkaloids taspine (1) and (-)-asimilobine (2), which were detected for the first time in this species. Compound 1 showed a significantly higher effect on AChE than the positive control galanthamine and selectively inhibited the enzyme in a long-lasting and concentration-dependent fashion with an IC(50) value of 0.33 +/- 0.07 muM. Extensive molecular docking studies were performed with human and Torpedo californica-AChE employing Gold software to rationalize the binding interaction. The results suggested ligand 1 to bind in an alternative binding orientation when compared to galanthamine. While this is located in close vicinity to the catalytic amino acid triad, the 1-AChE complex was found to be stabilized by (i) sandwich-like pi-stacking interactions between the planar aromatic ligand (1) and the Trp84 and Phe330 of the enzyme, (ii) an esteratic site anchoring with the amino side chain, and (iii) a hydrogen-bonding network.
Rollinger
Judith M
JM
Institute of Pharmacy/Pharmacognosy, Center for Molecular Biosciences Innsbruck, Innrain 52c, Leopold Franzens-Universität, A-6020 Innsbruck, Austria. judith.rollinger@uibk.ac.at
Schuster
Daniela
D
Baier
Elisabeth
E
Ellmerer
Ernst P
EP
Langer
Thierry
T
Stuppner
Hermann
H
D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D001317:Austria; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004593:Electrophorus / Q000378:metabolism; D005702:Galantamine / Q000494:pharmacology; D006860:Hydrogen Bonding; D008024:Ligands; D031566:Magnolia / Q000737:chemistry*; D024301:Plant Bark / Q000737:chemistry; D018515:Plant Leaves / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry*
D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D008024:Ligands; D005702:Galantamine; C018394:taspine