ACHE and Alzheimer disease: In1993, Sussman and Silman solved the crystal structure of TcAChEin complex with tacrine, the first approved anti-AD drug,11 and 4 years later the structure of the complexwith the natural product (−)-huperzine A.12 Tacrine and (−)-huperzine A occupy adjacent bindingsites within the CAS of AChE, which overlap only partially (Figure 2A,B).