4B80

Mus musculus Acetylcholinesterase in complex with N-(2-Diethylamino-ethyl)-1-(4-fluoro-phenyl)-methanesulfonamide

Summary for 4B80

• Entry DOI: 10.2210/pdb4b80/pdb
• Related: 1C2B 1C2O 1J06 1J07 1KU6 1MAA 1MAH 1N5M 1N5R 1Q83 1Q84 2C0P 2C0Q 2H9Y 2HA0 2HA2 2HA3 2HA4 2HA5 2HA6 2HA7 2JEY 2JEZ 2JF0 2JGE 2JGF 2JGG 2JGH 2JGI 2JGJ 2JGK 2JGL 2JGM 2WHP 2WHQ 2WHR 2WLS 2WU3 2WU4 2XUD 2XUF 2XUG 2XUH 2XUI 2XUJ 2XUK 2XUO 2XUP 2XUQ 4A16 4A23 4ARA 4ARB 4B7Z 4B81 4B82 4B83 4B84 4B85
• Descriptor: ACETYLCHOLINESTERASE, N-[2-(diethylamino)ethyl]-1-(4-fluorophenyl)methanesulfonamide, 1,2-ETHANEDIOL, ... (9 entities in total)
• Functional Keywords: hydrolase, inhibitor
• Biological source: MUS MUSCULUS (HOUSE MOUSE)
• Total number of polymer chains: 2
• Total formula weight: 123534.32

Authors

Andersson, C.D.,Forsgren, N.,Akfur, C.,Allgardsson, A.,Berg, L.,Qian, W.,Ekstrom, F.,Linusson, A. (deposition date: 2012-08-24, release date: 2013-09-04, Last modification date: 2024-10-16)

Primary citation

Andersson, C.D.,Forsgren, N.,Akfur, C.,Allgardsson, A.,Berg, L.,Engdahl, C.,Qian, W.,Ekstrom, F.,Linusson, A.
Divergent structure-activity relationships of structurally similar acetylcholinesterase inhibitors.
J. Med. Chem., 56:7615-7624, 2013

PubMed 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.

PubMed: 23984975
DOI: 10.1021/jm400990p

Experimental method

X-RAY DIFFRACTION (2.5 Å)