Download MendeleySlow-Binding Inhibition of Acetylcholinesterase by a 6-Methyluracil Alkyl-Ammonium Derivative: Mechanism and Advantages for Myasthenia Gravis Treatment.
Kharlamova, A.D., Lushchekina, S.V., Petrov, K.A., Kots, E.D., Nachon, F.V., Villard-Wandhammer, M., Zueva, I.V., Krejci, E., Reznik, V.S., Zobov, V.V., Nikolsky, E.E., Masson, P.(2016) Biochem J 473: 1225
- PubMed: 26929400
- DOI: https://doi.org/10.1042/BCJ20160084
- Primary Citation of Related Structures:
5FKJ - PubMed 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 ? 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.
Organizational Affiliation:
A.E. Arbuzov Institute of Organic and Physical Chemistry of Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088 Russia.
