Reaction site-driven regioselective synthesis of AChE inhibitors.
The enzyme-directed synthesis is an emerging fragment-based lead discovery approach in which the biological target is able to assemble its own multidentate ligands from a pool of building blocks. Here, we report for the first time the use of the human acetylcholinesterase (AChE) as an enzyme for the design and synthesis of new potent heterodimeric huprine-based inhibitors. Both the specific click chemistry site within the protein and the regioselectivity of the Huisgen cycloaddition observed suggest promising alternatives in the design of efficient mono- and dimeric ligands of AChE. Finally, a detailed computational modelling of the click reaction was conducted to further understand the origin of this TGS selectivity.
Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, 1 rue Tesnière 76821 Mont-Saint-Aignan, Cedex, France. pierre-yves.renard@univ-rouen.fr.
Emilia
E
Oueis
Gianluca
G
Santoni
Cyril
C
Ronco
Olga
O
Syzgantseva
Vincent
V
Tognetti
Laurent
L
Joubert
Anthony
A
Romieu
Martin
M
Weik
Ludovic
L
Jean
Cyrille
C
Sabot
Florian
F
Nachon
Pierre-Yves
PY
Renard
D000110:Acetylcholinesterase / Q000378:metabolism*; D000634:Aminoquinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D057930:Click Chemistry; D003500:Cyclization; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism
D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D008024:Ligands; D011994:Recombinant Proteins; D000110:Acetylcholinesterase