Inhibition of AChE: structure-activity relationship among conformational transition of Trp84 and biomolecular rate constant.

C Bertonati, M Marta, M Patamia, A Colella, M Pomponi
{"title":"Inhibition of AChE: structure-activity relationship among conformational transition of Trp84 and biomolecular rate constant.","authors":"C Bertonati,&nbsp;M Marta,&nbsp;M Patamia,&nbsp;A Colella,&nbsp;M Pomponi","doi":"10.3109/14756360009040709","DOIUrl":null,"url":null,"abstract":"<p><p>In this study the authors attempt to correlate kinetic constants for carbamylation of AChE, by a series of carbamate inhibitors, with the conformational positioning of Trp84 in transition state complexes of the same carbamates with Torpedo AChE, as obtained by computerized molecular modelling. They present evidence for changes in the distance of the carbamates from the center of the indole ring which can be correlated with the bimolecular rate constants for inhibition. As a result the greater the distance from Trp84, the smaller the bimolecular inhibition constant value, ki (= k2/Ka), becomes. In conclusion, the value of the bimolecular rate constant for selected AChE inhibitors (structural changes that have been hypothesised or natural alkaloids of unknown activity) which possess similar size and rigidity, can be obtained. Under these conditions energy minimization alone seems to be sufficient even to accurately predict protein-substrate interactions that actually occur. Modelling studies also suggest that conformational re-orientation of Trp84 in the transition state could produce an overall movement of the Cys67-Cys94 loop.</p>","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"15 6","pages":"547-56"},"PeriodicalIF":0.0000,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3109/14756360009040709","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of enzyme inhibition","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3109/14756360009040709","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 1

Abstract

In this study the authors attempt to correlate kinetic constants for carbamylation of AChE, by a series of carbamate inhibitors, with the conformational positioning of Trp84 in transition state complexes of the same carbamates with Torpedo AChE, as obtained by computerized molecular modelling. They present evidence for changes in the distance of the carbamates from the center of the indole ring which can be correlated with the bimolecular rate constants for inhibition. As a result the greater the distance from Trp84, the smaller the bimolecular inhibition constant value, ki (= k2/Ka), becomes. In conclusion, the value of the bimolecular rate constant for selected AChE inhibitors (structural changes that have been hypothesised or natural alkaloids of unknown activity) which possess similar size and rigidity, can be obtained. Under these conditions energy minimization alone seems to be sufficient even to accurately predict protein-substrate interactions that actually occur. Modelling studies also suggest that conformational re-orientation of Trp84 in the transition state could produce an overall movement of the Cys67-Cys94 loop.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
AChE的抑制:Trp84构象转变与生物分子速率常数的构效关系。
在这项研究中,作者试图将一系列氨基甲酸酯抑制剂对乙酰氨基甲酸酯氨基化的动力学常数与Trp84在相同氨基甲酸酯与鱼雷乙酰氨基甲酸酯的过渡态络合物中的构象定位联系起来,这是通过计算机分子模型获得的。他们提出了氨基甲酸酯与吲哚环中心距离变化的证据,这与抑制的双分子速率常数有关。结果表明,与Trp84的距离越大,双分子抑制常数ki (= k2/Ka)越小。综上所述,可以获得具有相似大小和硬度的所选AChE抑制剂(假设的结构变化或活性未知的天然生物碱)的双分子速率常数值。在这些条件下,能量最小化似乎足以准确预测实际发生的蛋白质-底物相互作用。模拟研究还表明,Trp84在过渡状态下的构象重新定向可能导致Cys67-Cys94环的整体运动。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
Progress Curves Analysis as an Alternative for Exploration of Activation-inhibition Phenomena in Cholinesterases Enantioselectivity of Some 1-[(Benzofuran-2-yl) phenylmethyl] imidazoles as Aromatase (P450AROM) Inhibitors Protective Effects of Suprofen and its Methyl Ester Against Inactivation of Rabbit Kidney Carbonyl Reductase by Phenylglyoxal Inhibition of Potato Polyphenol Oxidase by Anions and Activity in Various Carboxylate Buffers (pH 4.8) at Constant Ionic Strength Stable Expression of the Human 5α-Reductase Isoenzymes Type I and Type II in HEK293 Cells to Identify Dual and Selective Inhibitors
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1