jm400990p_si_001.pdf (4.09 MB)
Divergent Structure–Activity Relationships of Structurally Similar Acetylcholinesterase Inhibitors
journal contribution
posted on 2013-10-10, 00:00 authored by C. David Andersson, Nina Forsgren, Christine Akfur, Anders Allgardsson, Lotta Berg, Cecilia Engdahl, Weixing Qian, Fredrik Ekström, Anna LinussonThe 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.