Interaction Between HA and AChE

The three-dimensional (3-D) computer image of AChE-HA binding generated in the Raves et al. study revealed how the HA blocks the enzyme by sliding smoothly into the active site of AChE where ACh is broken down, and how it latches onto this site via many subtle chemical links. It was also demonstrated that HA can form an extra hydrogen bond with lyr 337 within the choline site that exists only in mammalian AChE, but not in Torpedo enzyme and BuChE. The stronger inhibitory property of HA for mammalian AChE than for the other two enzymes may rely on this particular interaction. 

The x-ray stmcture of complexes of TcAChE with HA and other AChE inhibitors displayed that these noncovalent inhibitors vary greatly in their stmctures and bind to different sites of the enzyme, offering many different starting points for future dmg design. To rationalize the stmcmral requirements of AChE inhibitors, Kaur and Zhang attempted to derive a coherent AChE-inhibitor recognition pattern based on literature data of molecular modeling and quantitative SAR analyses. 

It is concluded that hydrophobicity and the presence of an ionizable nitrogen are the prerequisites for the inhibitors to interact with AChE. It is also recognized that water molecules play a cmcial role in defining these different 3-D positions. 

To date, more than 30 stmctures of the ligand-AChE complexes have been determined by x-ray crystallography (http //www.rcsb.org/pdb/index.html). Great efforts 

Considering that the bridgehead amino group of HA is not part of a direct interaction with TcAChE, Hogenauer et al. prepared 5-desamino HA (25j) and revealed that it had 100-fold less activity than HA, which indicates that the amino functionality is necessary for biological activity.  

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