Law Ken-Shing, Acey Roger A, Smith Cameron R, Benton David A, Soroushian Sheila, Eckenrod Brett, Stedman Rachael, Kantardjieff Katherine A, Nakayama Kensaku
Department of Chemistry and Biochemistry, California State University-Long Beach, 1250 Bellflower Blvd., Long Beach, CA 90840, USA.
Biochem Biophys Res Commun. 2007 Apr 6;355(2):371-8. doi: 10.1016/j.bbrc.2007.01.186. Epub 2007 Feb 8.
A series of dialkyl phenyl phosphates (DAPPs) were synthesized and evaluated in silico and in vitro for inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Among the compounds examined, several DAPPs were shown to be potent inhibitors of butyrylcholinesterase, while having little activity against acetylcholinesterase. The most potent and selective inhibitors were di-n-butyl phenyl phosphate (K(i)=43 microM), di-n-pentyl phenyl phosphate (K(i)=6 microM), and di-cyclohexyl phenyl phosphate (K(i)=7 microM), the first which was shown to be a competitive inhibitor while the latter two being partial competitive inhibitors. Flexible docking simulations suggested that relative binding affinities generally increased as a function of alkyl chain length, while the strength and nature of inhibitory activity depended on whether the compound bound deeply or midway in the active site gorge, or in the proposed peripheral site.
合成了一系列二烷基苯基磷酸酯（DAPPs），并在计算机模拟和体外实验中评估了它们对乙酰胆碱酯酶和丁酰胆碱酯酶的抑制活性。在所研究的化合物中，几种DAPPs显示出是丁酰胆碱酯酶的有效抑制剂，而对乙酰胆碱酯酶几乎没有活性。最有效的选择性抑制剂是二正丁基苯基磷酸酯（K(i)=43 microM）、二正戊基苯基磷酸酯（K(i)=6 microM）和二环己基苯基磷酸酯（K(i)=7 microM），第一种显示为竞争性抑制剂，而后两种为部分竞争性抑制剂。灵活对接模拟表明，相对结合亲和力通常随着烷基链长度的增加而增加，而抑制活性的强度和性质取决于化合物是深入结合在活性位点峡谷中、中间位置，还是在提议的外周位点。
