The effect of structural characteristics of Lycopodane-type alkaloids on their acetylcholinesterase inhibitory activity in silico

Club mosses are known to produce a variety of alkaloids with condensed polycyclic structures. The club moss Huperzia serrata, which has long been used in traditional Chinese medicine, produces huperzine A, a potent acetylcholinesterase inhibitor which is currently being evaluated for its clinical efficacy in management of Alzheimer's disease and vascular dementia. In a recent study by the present authors, 10 lycopodane-type alkaloids were isolated from an Icelandic collection of Lycopodium annotinum ssp. alpestre. Their structures were elucidated and the isolated alkaloids were evaluated for their in vitro inhibitory activity against acetylcholinesterase.1 Acetylcholinesterase inhibitory activities of natural lycopodane-type alkaloids isolated in the previous study were weak and the aim of this study was to investigate the structure-activity relationship further using in silico molecular modeling methods in order to find more active derivatives suitable for semi-synthesis. Structure-activity relationship was studied with the help of molecular modeling using Maestro, Glide and Pymol software. Novel binding orientation of annotine found in the docking study suggests the possibility of synthesis of analogues with increased potency. Docking studies of the 80 analogues of annotine that were designed using a model of EeAChE indicated that acylation of the tertiary hydroxy group of annotine may increase the activity via strong hydrogen bonds resembling those between the enzyme binding site and huperzine A.

Acknowledgements: The Icelandic Research Fund, The University of Iceland Research Fund, The Icelandic Research Fund for Graduate Students, and Th. Scheving Thorsteinsson Fund.

References: 1. Halldorsdottir, E.S. et al. (2009) Phytochemistry 71:149–157.