Huperzine A Complexed with Acetylcholinesterase

3D Structure of Huperzine A Complexed with Acetylcholinesterase (1vot) (see also AChE inhibitors and substrates (Part II))

Background

Qian Ceng Ta has been used for over 1000 years in China for treatment of contusions, strains, swellings, schizophrenia and myasthenia gravis. Shuangyiping[2], a tablet form of HupA produced from the extracts of Huperzia serrata, was developed in 1996 as a new drug for symptomatic treatment of Alzheimer’s disease in China. Compared with the other three FDA-approved drugs for the treatment of Alzheimer’s disease, Donepezil (Aricept, 1eve), Rivastigmine (Exelon, 1gqr), Galanthamine (Reminyl, 1dx6), HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action.

The structure of HupA shows some similarity to other known AChE inhibitors and substrates. The molecule is fairly rigid and contains an aromatic system as well as a primary amino group that is probably protonated at physiological pH. Various suggestions have been made with respect to its orientation within the active site of AChE, and with respect to the amino acid residue with which its putative pharmacophoric groups might interact. Solution of the 3D structure of a complex of HupA with AChE would permit unequivocal resolution of this issue and it would also provide a rational basis for structure-related drug design aimed at developing synthetic analogues of HupA with improved therapeutic properties.

Structure

The crystal structure of the complex of Torpedo californica AChE (TcAChE) with HupA at 2.5 Å resolution (pdb code 1vot) was determined in 1997 and it shows an unexpected orientation for the inhibitor with surprisingly few strong direct interactions with protein residues to explain its high affinity. The active site of TcAChE was found to be buried at the bottom of a , lined by (colored darkmagenta). The TcAChE natural substrate (ACh) directly binds within the (Ser200, His440, and Glu327). The residues are also important in the ligand recognition. HupA also binds to TcAChE at this active site, but its in comparison to ACh. The principal interactions of are including: a direct (colored orange) through a water molecule as a linker at the bottom of the gorge; cation-π interactions between the amino group of (colored lime) with the distance between the nitrogen and the centroid of the aromatic rings of 4.8 and 4.7 Å, respectively; at the top of the gorge, hydrogen bonds (HBs) through two water molecules as linkers formed between the amino group of (colored magenta). An unusually short (~3.0 Å) C-H→O HB has been seen between the ethylidene methyl group of (colored crimson).

Additional Resources

For additional information, see: Alzheimer's Disease