Identification of a more potent analogue of the naturally occurring alkaloid huperzine A. Predictive molecular modeling of its interaction with AChE

The synthesis and biology of certain C-10 substituted analogues were examined based on cumulative SAR data and to some extent the predicted binding site of huperzine A within Torpedo acetylcholinesterase (AChE). The introduction of constituents bigger than methyl produced a drop in activity. Molecular modeling methods involving the docking of these analogues to the X-ray crystal structure of Torpedo AChE showed that the C-10 axial methyl group points into a hydrophobic region on the enzyme.