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Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: mechanism and possible advantages for myasthenia gravis treatment.
Biochem J. 2016 05 01; 473(9):1225-36.BJ

Abstract

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.

Authors+Show Affiliations

A.E. Arbuzov Institute of Organic and Physical Chemistry of Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088 Russia.N.M. Emanuel Institute of Biochemical Physics of Russian Academy of Sciences, Moscow 119334, Russia.A.E. Arbuzov Institute of Organic and Physical Chemistry of Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088 Russia.N.M. Emanuel Institute of Biochemical Physics of Russian Academy of Sciences, Moscow 119334, Russia.Institut de Recherche Biomédicale des Armées, 91223 Brétigny-sur-Orge, France.Institut de Recherche Biomédicale des Armées, 91223 Brétigny-sur-Orge, France.A.E. Arbuzov Institute of Organic and Physical Chemistry of Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088 Russia.COGNition ACtion Group, CNRS, Université Paris Descartes 75006 Paris, France.A.E. Arbuzov Institute of Organic and Physical Chemistry of Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088 Russia.A.E. Arbuzov Institute of Organic and Physical Chemistry of Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088 Russia.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.Kazan Federal University, Neuropharmacology Lab., Kremlevskaia St. 18, Kazan 420000, Russia pym.masson@free.fr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26929400

Citation

Kharlamova, Alexandra D., et al. "Slow-binding Inhibition of Acetylcholinesterase By an Alkylammonium Derivative of 6-methyluracil: Mechanism and Possible Advantages for Myasthenia Gravis Treatment." The Biochemical Journal, vol. 473, no. 9, 2016, pp. 1225-36.
Kharlamova AD, Lushchekina SV, Petrov KA, et al. Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: mechanism and possible advantages for myasthenia gravis treatment. Biochem J. 2016;473(9):1225-36.
Kharlamova, A. D., Lushchekina, S. V., Petrov, K. A., Kots, E. D., Nachon, F., Villard-Wandhammer, M., Zueva, I. V., Krejci, E., Reznik, V. S., Zobov, V. V., Nikolsky, E. E., & Masson, P. (2016). Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: mechanism and possible advantages for myasthenia gravis treatment. The Biochemical Journal, 473(9), 1225-36. https://doi.org/10.1042/BCJ20160084
Kharlamova AD, et al. Slow-binding Inhibition of Acetylcholinesterase By an Alkylammonium Derivative of 6-methyluracil: Mechanism and Possible Advantages for Myasthenia Gravis Treatment. Biochem J. 2016 05 1;473(9):1225-36. PubMed PMID: 26929400.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: mechanism and possible advantages for myasthenia gravis treatment. AU - Kharlamova,Alexandra D, AU - Lushchekina,Sofya V, AU - Petrov,Konstantin A, AU - Kots,Ekaterina D, AU - Nachon,Florian, AU - Villard-Wandhammer,Marielle, AU - Zueva,Irina V, AU - Krejci,Eric, AU - Reznik,Vladimir S, AU - Zobov,Vladimir V, AU - Nikolsky,Evgeny E, AU - Masson,Patrick, Y1 - 2016/02/29/ PY - 2015/11/16/received PY - 2016/02/26/accepted PY - 2016/3/2/entrez PY - 2016/3/2/pubmed PY - 2017/6/9/medline KW - 6-methyluracil KW - X-ray structure KW - acetylcholinesterase KW - butyrylcholinesterase KW - molecular modelling KW - slow-binding inhibition SP - 1225 EP - 36 JF - The Biochemical journal JO - Biochem J VL - 473 IS - 9 N2 - 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. SN - 1470-8728 UR - https://www.unboundmedicine.com/medline/citation/26929400/Slow_binding_inhibition_of_acetylcholinesterase_by_an_alkylammonium_derivative_of_6_methyluracil:_mechanism_and_possible_advantages_for_myasthenia_gravis_treatment_ L2 - https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BCJ20160084 DB - PRIME DP - Unbound Medicine ER -