Merits and limits of computational methods for the discovery of natural acetylcholinesterase inhibitors

Bioactive natural products and drug substances in general exhibit their pharmacological activity by binding as ligands to biomolecular targets. Functions and 3D-structures of an increasing number of target macromolecules are becoming available. On the other hand, a wealth of potent ligands from both synthetic and natural origin provides a rich pool of structural and biological information. In this light, computational methods contribute to (i) a rapid identification of novel lead compounds and (ii) an improved molecular insight of ligand-target interactions. This study deals with the application of diverse integrated in silico tools to increase the efficiency in the search for natural acetylcholinesterase (AChE) inhibitors. In contrast to previous screening results, where we have been able to correctly predict novel bioactive natural products from in house molecular 3D libraries [1, 2], we report here on the limitations of pharmacophore based virtual screening. A highly potent anticholinesterase alkaloid, taspine (IC₅₀ 333±70 nM), was isolated by bio-guided fractionation from Magnolia x soulangiana Soul.-Bod. However, none of the 3D conformers was able to fit into the elaborated pharmacophore model [1]. Extensive docking studies on human- and Torpedo californica-AChE strongly suggest a binding mode of taspine, which is different to that of known ligands in the active binding site (e.g. galanthamine; [3]) and in the peripheral anionic binding site [4]. It may be assumed that taspine does not occupy the catalytic center itself but prevents acetylcholine from accurately being positioned in the binding pocket for cleavage. Concluding, molecular docking studies helped to explore the possible binding mode of taspine as “hydrophobic plug“ in the aromatic gorge of AChE.

Acknowledgements: This work was granted by the FWF Austria (P18379)

References: 1. Rollinger, J.M. et al. (2004), J. Med. Chem. 47: 6248–6254. 2. Rollinger, J.M. et al. (2005), Curr. Drug Disc. Techn. 2: 185–193. 3. Greenblatt, H.M. et al. (2004), J. Am. Chem. Soc. 126: 15405–15411. 4. Kryger, G. et al. (2000), Acta Crystallogr. D 56: 1385–1394.