Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: mechanism and possible advantages for myasthenia gravis treatment.

Autor:	Kharlamova AD; A.E. Arbuzov Institute of Organic and Physical Chemistry of Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088 Russia., Lushchekina SV; N.M. Emanuel Institute of Biochemical Physics of Russian Academy of Sciences, Moscow 119334, Russia., Petrov KA; A.E. Arbuzov Institute of Organic and Physical Chemistry of Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088 Russia., Kots ED; N.M. Emanuel Institute of Biochemical Physics of Russian Academy of Sciences, Moscow 119334, Russia., Nachon F; Institut de Recherche Biomédicale des Armées, 91223 Brétigny-sur-Orge, France., Villard-Wandhammer M; Institut de Recherche Biomédicale des Armées, 91223 Brétigny-sur-Orge, France., Zueva IV; A.E. Arbuzov Institute of Organic and Physical Chemistry of Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088 Russia., Krejci E; COGNition ACtion Group, CNRS, Université Paris Descartes 75006 Paris, France., Reznik VS; A.E. Arbuzov Institute of Organic and Physical Chemistry of Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088 Russia., Zobov VV; A.E. Arbuzov Institute of Organic and Physical Chemistry of Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088 Russia., Nikolsky EE; Kazan Institute of Biochemistry and Biophysics of Russian Academy of Sciences, P.O. Box 30, Kazan 420111, Russia Kazan Federal University, Neuropharmacology Lab., Kremlevskaia St. 18, Kazan 420000, Russia., Masson P; Kazan Federal University, Neuropharmacology Lab., Kremlevskaia St. 18, Kazan 420000, Russia pym.masson@free.fr.
Jazyk:	angličtina
Zdroj:	The Biochemical journal [Biochem J] 2016 May 01; Vol. 473 (9), pp. 1225-36. Date of Electronic Publication: 2016 Feb 29.
DOI:	10.1042/BCJ20160084
Abstrakt:	Inhibition of human AChE (acetylcholinesterase) and BChE (butyrylcholinesterase) by an alkylammonium derivative of 6-methyluracil, C-547, a potential drug for the treatment of MG (myasthenia gravis) was studied. Kinetic analysis of AChE inhibition showed that C-547 is a slow-binding inhibitor of type B, i.e. after formation of the initial enzyme·inhibitor complex (Ki=140 pM), an induced-fit step allows establishment of the final complex (Ki*=22 pM). The estimated koff is low, 0.05 min(-1) On the other hand, reversible inhibition of human BChE is a fast-binding process of mixed-type (Ki=1.77 μM; Ki'=3.17 μM). The crystal structure of mouse AChE complexed with C-547 was solved at 3.13 Å resolution. The complex is stabilized by cation-π, stacking and hydrogen-bonding interactions. Molecular dynamics simulations of the binding/dissociation processes of C-547 and C-35 (a non-charged analogue) to mouse and human AChEs were performed. Molecular modelling on mouse and human AChE showed that the slow step results from an enzyme conformational change that allows C-547 to cross the bottleneck in the active-site gorge, followed by formation of tight complex, as observed in the crystal structure. In contrast, the related non-charged compound C-35 is not a slow-binding inhibitor. It does not cross the bottleneck because it is not sensitive to the electrostatic driving force to reach the bottom of the gorge. Thus C-547 is one of the most potent and selective reversible inhibitors of AChE with a long residence time, τ=20 min, longer than for other reversible inhibitors used in the treatment of MG. This makes C-547 a promising drug for the treatment of this disease. (© 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
Databáze:	MEDLINE
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