Chemistry Reference
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formation of the AChE-HA complex is rapid, and the dissociation is slow.
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This
complex has been studied with kinetic, computer-aided docking and x-ray crystal-
lography approaches.
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 Tyr 337 within the choline site
that exists only in mammalian AChE, but not in Torpedo enzyme and BuChE.
146,147
The stronger inhibitory property of HA for mammalian AChE than for the other two
enzymes may rely on this particular interaction.
Xu et al. investigated how HA enter and leave the binding gorge of AChE
with steered molecular dynamics (SMD)
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simulations.
149
The analysis of the
force required along the pathway shows that it is easier for HA to bind to the active
site of AChE than to disassociate from it, which interprets at the atomic level
the previous experimental result that the unbinding process of HA is much slower
than its binding process to AChE. The direct hydrogen bonds, water bridges, and
hydrophobic interactions were analyzed during two SMD simulations. The break
of the direct hydrogen bond needs a great pulling force. The steric hindrance of the
bottleneck might be the most important factor for producing the maximal rupture
force for HA to leave the binding site, but it has little effect on the binding process
of HA with AChE. Residue Asp72 forms a lot of water bridges, with HA leaving
and entering the AChE binding gorge, acting as a clamp to take out HA from or put
HA into the active site. The flip of the peptide bond between Gly117 and Gly118
has been detected during both the conventional MD and the SMD simulations. The
simulation results indicate that this flip phenomenon could be an intrinsic property
of AChE, and the Gly117-Gly118 peptide bond in both HA bound and unbound
AChE structures tends to adopt the native enzyme structure. Finally, in a vacuum, the
rupture force is increased up to 1500 pN, whereas in a water solution, the greatest
rupture force is about 800 pN, which means water molecules in the binding gorge act
as a lubricant to facilitate HA entering or leaving the binding gorge.
4.7.2
Structure-Based HA Analog Design
The x-ray structure of complexes of TcAChE with HA and other AChE inhibitors
displayed that these noncovalent inhibitors vary greatly in their structures and bind
to different sites of the enzyme, offering many different starting points for future
drug design. To rationalize the structural 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.
150
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 crucial role in defining these different 3-D positions.
To date, more than 30 structures of the ligand-AChE complexes have been deter-
mined by x-ray crystallography (http://www.rcsb.org/pdb/index.html). Great efforts
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