4B85: Mus musculus Acetylcholinesterase in complex with 4-Chloranyl-N-(2- diethylamino-ethyl)-benzenesulfonamide

Citation:
Abstract
The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N-[2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure-activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X-ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE.
PDB ID: 4B85Download
MMDB ID: 113146
PDB Deposition Date: 2012/8/24
Updated in MMDB: 2013/10
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 4B85: dimeric; determined by author and by software (PISA)
Molecular Components in 4B85
Label Count Molecule
Proteins (2 molecules)
2
Acetylcholinesterase(Gene symbol: Ache)
Molecule annotation
Chemicals (15 molecules)
1
2
2
2
3
8
4
2
5
1
* Click molecule labels to explore molecular sequence information.

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