Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators.
Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators.
复制标题
亚烷基连接的双吡啶醛肟作为改进的乙酰胆碱酯酶再激活剂的合理设计。
DOI：
10.1016/s1074-5521(03)00126-1
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发表时间：
2003
影响因子：
--
通讯作者：
Brimijoin,Stephen
中科院分区：
文献类型：
--
作者：
Pang,Yuan-Ping;Kollmeyer,ThomasM;Hong,Feng;Lee,Jong-Cheol;Hammond,PamelaI;Haugabouk,SharieP;Brimijoin,Stephen
To improve the potency of 2-pralidoxime (2-PAM) for treating organophosphate poisoning, we dimerized 2-PAM and its analogs according to Wilson's pioneering work and the 3D structure of human acetylcholinesterase (hAChE) inactivated by isoflurophate. 1,7-Heptylene-bis-N,N'-syn-2-pyridiniumaldoxime, the most potent of the alkylene-linked dimeric reactivators, was readily synthesized using bistriflate and is 100 times more potent than 2-PAM in reactivating hAChE poisoned by isoflurophate. Experimental and computational studies confirm that 2-PAM in its biologically active form adopts thesyn-I configuration. Further, they suggest that the improved performance of dimeric oximes is conferred by two-site binding with one oxime pointing toward the diisopropyl ester at the catalytic site of hAChE and the other anchored at the peripheral site. This type of binding may induce a conformational change in the acyl pocket loop which modulates the catalytic site via a domino effect.
