Technical Pitfalls and Improvements for High-speed Screening and QSAR Analysis to Predict Inhibitors of the Human Bile Salt Export Pump (ABCB11/BSEP)
Technical Pitfalls and Improvements for High-speed Screening and QSAR Analysis to Predict Inhibitors of the Human Bile Salt Export Pump (ABCB11/BSEP)
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用于预测人类胆盐输出泵抑制剂的高速筛选和 QSAR 分析的技术陷阱和改进 (ABCB11/BSEP)
DOI：
10.1208/s12248-009-9137-9
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
T. Ishikawa
中科院分区：
文献类型：
--
作者：
H. Saito;M. Osumi;H. Hirano;Wangsoo Shin;Ryota Nakamura;T. Ishikawa
药物性肝毒性是药物发现和开发中遇到的主要问题之一。在药物发现过程中，为临床前研究选择候选化合物是决定临床开发速度和费用的关键步骤。由于抑制人三磷酸腺苷结合盒转运体ABCB 11（SPGP/胆盐输出泵）具有严重的后果，包括肝内胆汁淤积和肝毒性，导致暴露于有毒的外源性物质或药物相互作用，体外筛选方法是必要的定量和表征ABCB 11的抑制。根据这些举措，我们开发了体外高速筛选和定量构效关系（QSAR）分析的方法，以研究ABCB 11与各种化合物的相互作用。我们确定了一组与ABCB 11抑制密切相关的化学片段化代码。此外，高速筛选方法使我们能够通过测试化合物分析ABCB 11抑制的动力学，并区分竞争性和非竞争性抑制剂。发现曲格列酮和新生霉素是牛磺胆酸盐的竞争性抑制剂，而卟啉是非竞争性抑制剂。基于动力学的抑制剂分类被认为是重要的，以提高我们的QSAR分析的准确性。目前的小型审查地址的技术缺陷和改进的高速筛选和定量构效关系分析的ABCB 11抑制研究。
Drug-induced hepatotoxicity is one of the major problems encountered in drug discovery and development. Selection of a candidate compound for pre-clinical studies in the drug discovery process is a critical step that can determine the speed and expenditure of clinical development. Because inhibition of human adenosine triphosphate-binding cassette transporter ABCB11 (SPGP/bile salt export pump) has severe consequences, which include intrahepatic cholestasis and hepatotoxicity, resulting from exposure to toxic xenobiotics or drug interactions, in vitro screening methods are necessary for quantifying and characterizing the inhibition of ABCB11. In line with such initiatives, we developed methods for in vitro high-speed screening and quantitative structure-activity relationship (QSAR) analysis to investigate the interaction of ABCB11 with a variety of compounds. We identified one set of chemical fragmentation codes closely linked with inhibition of ABCB11. Furthermore, the high-speed screening method enables us to analyze the kinetics of ABCB11-inhibition by test compounds and to distinguish competitive and non-competitive inhibitors. Troglitazone and novobiocin were found to be competitive inhibitors to taurocholate, whereas porphyrins were non-competitive inhibitors. Kinetics-based classification of inhibitors is considered important to improve the accuracy of our QSAR analysis. The present mini-review addresses technical pitfalls and improvements for high-speed screening and QSAR analysis in the ABCB11 inhibition study.
影响因子：
3.7
作者：
Gary R. Whittaker;Ari Helenius
通讯作者：
Gary R. Whittaker;Ari Helenius
影响因子：
3.7
作者：
Lanier, LM;Volkman, LE
通讯作者：
Volkman, LE
DOI：
10.1152/ajpgi.00491.2002
发表时间：
2003-05-01
影响因子：
4.5
作者：
Higuchi, H;Gores, GJ
通讯作者：
Gores, GJ