Computational screening and QSAR analysis for design of AMP-activated protein kinase agonist
Computational screening and QSAR analysis for design of AMP-activated protein kinase agonist
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DOI：
10.1016/j.jtice.2009.09.002
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发表时间：
2010-05-01
影响因子：
5.7
通讯作者：
Chen, Calvin Yu-Chian
中科院分区：
文献类型：
--
作者：
Huang, Hung-Jin;Chen, Chien-Yu;Chen, Calvin Yu-Chian
AMP激活的蛋白激酶(AMPK)通过监测各种真核生物中的AMP来感知细胞的能量状态。激活的AMPK调节引起糖尿病、肥胖症、代谢异常以及乳腺癌的一系列重要途径。本研究以酵母AMPK的晶体结构为模板，构建了人AMPK与相应结合部位的同源模型。利用定量构效关系(QSAR)模型、比较分子场分析(CoMFA)模型和比较分子相似指数分析(CoMSIA)模型获得了药效团的特征。通过对数据的虚拟筛选，筛选出“德新星进化”筛选出的前8位苯酰胺类化合物，为AMPK设计新的配体。随后总共产生了531种衍生品。与AMP和AICAR一样，所有的强效配体都带有与AMPK的关键相互作用氨基酸相互作用的氢键。用CoMFA和CoMSIA模型对衍生物的性质进行了拟合。因此，这些数据表明苯酰胺类化合物可能是AMPK激动剂。(C)2009年台湾化学工程师学会。爱思唯尔出版，版权所有。
AMP-activated protein kinase (AMPK) senses the cellular energy state by monitoring the AMP in various eukaryotes. The activated AMPK regulates a wide range of important pathways which cause diabetes, obesity, metabolic aberrant, and also breast cancer. In this study, the crystal structure of yeast AMPK was used as a template to construct the reliable homology model of human AMPK with corresponding binding site. The quantitative structure-activity relationship (QSAR) models, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models, were utilized to obtain the pharmacophore feature. By virtual screening the data, the top eight phenylamide compounds screened by "De nova evolution" were selected to design new ligands for AMPK. A total of 531 derivatives were generated subsequently. All the potent ligands, same as AMP and AICAR, carried H-bond interacting with the key interactive amino acids of AMPK. The features of the derivatives were also fitted with the CoMFA and CoMSIA models. Thus, these data suggested that the phenylamide derivates might be the potent AMPK agonists. (C) 2009 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.