On May 1, 2016, Kharlamova, Alexandra D.; Lushchekina, Sofya V.; Petrov, Konstantin A.; Kots, Ekaterina D.; Nachon, Florian; Villard-Wandhammer, Marielle; Zueva, Irina V.; Krejci, Eric; Reznik, Vladimir S.; Zobov, Vladimir V.; Nikolsky, Evgeny E.; Masson, Patrick published an article.Electric Literature of 626-48-2 The title of the article was Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: mechanism and possible advantages for myasthenia gravis treatment. And the article contained the following:
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 anal. 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. Mol. dynamics simulations of the binding/dissociation processes of C-547 and C-35 (a non-charged analog) to mouse and human AChEs were performed. Mol. modeling 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. The experimental process involved the reaction of 6-Methylpyrimidine-2,4(1H,3H)-dione(cas: 626-48-2).Electric Literature of 626-48-2
The Article related to myasthenia gravis acetylcholinesterase alkyl ammonium 6 methyl uracil, 6-methyluracil, x-ray structure, acetylcholinesterase, butyrylcholinesterase, molecular modelling, slow-binding inhibition and other aspects.Electric Literature of 626-48-2
Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia