{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:37:54Z","timestamp":1783039074027,"version":"3.54.6"},"reference-count":54,"publisher":"Portland Press Ltd.","issue":"9","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,5,1]]},"abstract":"<jats:p>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\u00a0B, i.e. after formation of the initial enzyme\u00b7inhibitor 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\u22121. On the other hand, reversible inhibition of human BChE is a fast-binding process of mixed-type (Ki=1.77\u00a0\u03bcM; Ki\u2032=3.17\u00a0\u03bcM). The crystal structure of mouse AChE complexed with C-547 was solved at 3.13 \u00c5 resolution. The complex is stabilized by cation\u2013\u03c0, 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, \u03c4=20\u00a0min, 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.<\/jats:p>","DOI":"10.1042\/bcj20160084","type":"journal-article","created":{"date-parts":[[2016,3,1]],"date-time":"2016-03-01T03:14:32Z","timestamp":1456802072000},"page":"1225-1236","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: mechanism and possible advantages for myasthenia gravis treatment"],"prefix":"10.1042","volume":"473","author":[{"given":"Alexandra\u00a0D.","family":"Kharlamova","sequence":"first","affiliation":[{"name":"A.E. 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