Andersson_2013_J.Med.Chem_56_7615

Reference

Title : Divergent Structure-Activity Relationships of Structurally Similar Acetylcholinesterase Inhibitors - Andersson_2013_J.Med.Chem_56_7615
Author(s) : Andersson CD , Forsgren N , Akfur C , Allgardsson A , Berg L , Engdahl C , Qian W , Ekstrom F , Linusson A
Ref : Journal of Medicinal Chemistry , 56 :7615 , 2013
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.

PubMedSearch : Andersson_2013_J.Med.Chem_56_7615
PubMedID: 23984975
Gene_locus related to this paper: mouse-ACHE

Related information

Inhibitor CHEMBL3087804    CHEMBL3087808    CHEMBL3087813    CHEMBL3087814    CHEMBL3087815    CHEMBL1624646    CHEMBL3087807    CHEMBL3087806
Gene_locus CHEMBL3087804    CHEMBL3087808    CHEMBL3087813    CHEMBL3087814    CHEMBL3087815    CHEMBL1624646    CHEMBL3087807    CHEMBL3087806    mouse-ACHE
Structure CHEMBL3087804    CHEMBL3087808    CHEMBL3087813    CHEMBL3087814    CHEMBL3087815    CHEMBL1624646    CHEMBL3087807    CHEMBL3087806    mouse-ACHE    4BTL    4B7Z    4B80    4B81    4B82    4B83    4B84    4B85

Citations formats

Andersson CD, Forsgren N, Akfur C, Allgardsson A, Berg L, Engdahl C, Qian W, Ekstrom F, Linusson A (2013)
Divergent Structure-Activity Relationships of Structurally Similar Acetylcholinesterase Inhibitors
Journal of Medicinal Chemistry 56 :7615

Andersson CD, Forsgren N, Akfur C, Allgardsson A, Berg L, Engdahl C, Qian W, Ekstrom F, Linusson A (2013)
Journal of Medicinal Chemistry 56 :7615