Advancement of structure-activity relationship of multidrug resistance-associated protein 2 interactions

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.