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

- RUS
- 中文
- ES

SLOW-BINDING INHIBITION OF ACETYLCHOLINESTERASE BY AN ALKYLAMMONIUM DERIVATIVE OF 6-METHYLURACIL: MECHANISM AND POSSIBLE ADVANTAGES FOR MYASTHENIA GRAVIS TREATMENT

Form of presentation

Articles in international journals and collections

Year of publication

2016

��

��

Authors, employees of KFU

Petrov Konstantin Aleksandrovich, author

Bibliographic description in the original language

Kharlamova A.D. Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: Mechanism and possible advantages for myasthenia gravis treatment / A.D. Kharlamova, S.V. Lushchekina, K.A. Petrov, E.D. Kots, F.Nachon, M. Villard-Wandhammer, I.V. Zueva, E. Krejci, V.S. Reznik, V.V. Zobov, E.E. Nikolsky, P. Masson // Biochemical Journal, Volume 473, Issue 9, 1 May 2016, Pages 1225-1236

Annotation

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 -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 hydrogenbonding interactions. Molecular dynamics simulations of the binding/dissociation processes of C-547 and C-35 (a noncharged analogue) to mouse and human AChEs were performed.

Keywords

6-methyluracil; Acetylcholinesterase; Butyrylcholinesterase; Molecular modelling; Slow-binding inhibition; X-ray structure.

The name of the journal

BIOCHEMICAL JOURNAL

Please use this ID to quote from or refer to the card

https://repository.kpfu.ru/eng/?p_id=136583&p_lang=2

Full metadata record

Field DC	Value	Language
dc.contributor.author	Petrov Konstantin Aleksandrovich	ru_RU
dc.date.accessioned	2016-01-01T00:00:00Z	ru_RU
dc.date.available	2016-01-01T00:00:00Z	ru_RU
dc.date.issued	2016	ru_RU
dc.identifier.citation	Kharlamova A.D. Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: Mechanism and possible advantages for myasthenia gravis treatment / A.D. Kharlamova, S.V. Lushchekina, K.A. Petrov, E.D. Kots, F.Nachon, M. Villard-Wandhammer, I.V. Zueva, E. Krejci, V.S. Reznik, V.V. Zobov, E.E. Nikolsky, P. Masson // Biochemical Journal, Volume 473, Issue 9, 1 May 2016, Pages 1225-1236	ru_RU
dc.identifier.uri	https://repository.kpfu.ru/eng/?p_id=136583&p_lang=2	ru_RU
dc.description.abstract	BIOCHEMICAL JOURNAL	ru_RU
dc.description.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 -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 hydrogenbonding interactions. Molecular dynamics simulations of the binding/dissociation processes of C-547 and C-35 (a noncharged analogue) to mouse and human AChEs were performed.	ru_RU
dc.language.iso	ru	ru_RU
dc.subject		ru_RU
dc.title	Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: Mechanism and possible advantages for myasthenia gravis treatment	ru_RU
dc.type	Articles in international journals and collections	ru_RU