Xing Li, Hu Yiding, Lai Yurong
St Louis Laboratories, Pfizer Global Research and Development, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA.
AAPS J. 2009 Sep;11(3):406-13. doi: 10.1208/s12248-009-9117-0. Epub 2009 Jun 3.
Multidrug resistance-associated protein 2 (MRP2/ABCC2) is mainly expressed in the apical phase of barrier membranes. It functions as a critical efflux pump in the biliary excretion of endogenous substances, such as conjugated bilirubin and bile salts, as well as many structurally diverse xenobiotics and their metabolites. Due to its important role in defining ADME/Tox properties, efforts have emerged to build the structure-activity relationship (SAR) for MRP2/ABCC2 at early stages of drug discovery process. MRP2/ABCC2 is a member of the integral membrane protein family whose high-resolution crystal structure has not been described. To overcome the obstacle of lacking detailed structural depiction, various molecular modeling approaches have been applied to derive the structural requirements for binding interactions with MRP2/ABCC2 protein, including two-dimensional (2D) and three-dimensional (3D) quantitative SAR (QSAR) analysis, pharmacophore models, and homology modeling of the transporter. Here we summarize recent progresses in understanding the SAR of MRP2/ABCC2 recognition of substrates and/or inhibitors, and describe some of the useful in vitro tools for characterizing the interactions with the transporter.
多药耐药相关蛋白2（MRP2/ABCC2）主要表达于屏障膜的顶端。它作为一种关键的外排泵，参与内源性物质如结合胆红素和胆盐的胆汁排泄，以及许多结构多样的外源性物质及其代谢产物的排泄。由于其在定义药物的吸收、分布、代谢、排泄/毒性（ADME/Tox）特性方面的重要作用，人们在药物发现过程的早期就开始努力构建MRP2/ABCC2的构效关系（SAR）。MRP2/ABCC2是整合膜蛋白家族的成员，其高分辨率晶体结构尚未得到描述。为了克服缺乏详细结构描述的障碍，人们应用了各种分子建模方法来推导与MRP2/ABCC2蛋白结合相互作用的结构要求，包括二维（2D）和三维（3D）定量构效关系（QSAR）分析、药效团模型以及该转运蛋白的同源建模。在此，我们总结了在理解MRP2/ABCC2识别底物和/或抑制剂的构效关系方面的最新进展，并描述了一些用于表征与该转运蛋白相互作用的有用体外工具。
