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Correia, I ; Ronzani, N ; Platzer, N ; Doan, BT ; Beloeil, JC

Study of a potential inhibitor of acetylcholinesterase using UV spectrophotometry, NMR spectroscopy and molecular modeling

Journal of Physical Organic Chemistry 19 (2) 148-156

par Administrateur - publié le

Abstract :

1-[6-(Acridine-9-carbonyloxy)hexyl]pyridinium chloride (1) was synthesized and studied as a potential inhibitor of acetylcholinesterase (AChE), which is frequently involved in Alzheimer’s disease. UV spectrophotometry showed that 1 is a reversible and competitive inhibitor of AChE (K-i approximate to 2 x 10(-7) M). NMR (TrNOESY) showed that 1, bonded to AChE, maintains an extended form that allows hydrophobic interactions to occur between the aliphatic chain and the deep and narrow gorge of AchE and favors interactions between the acridine group and the catalytic and anionic subsites situated at the bottom of the gorge, and also between the pyridinium ring and the peripheral site. A more detailed picture of the structure of the complex was obtained by combining NMR structural data and molecular modeling (docking, dynamics simulation and energy calculations). Copyright (c) 2006 John Wiley & Sons, Ltd.