A Fluorescence Displacement Assay for Antidepressant Drug Discovery Based on Ligand-Conjugated Quantum Dots

作者：Chang Jerry C; Tomlinson Ian D; Warnement Michael R; Iwamoto Hideki; DeFelice Louis J; Blakely Randy D; Rosenthal Sandra J^*

来源：Journal of the American Chemical Society, 2011, 133(44): 17528-17531.

DOI：10.1021/ja204301g

The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) protein plays a central role in terminating 5-HT neurotransmission and is the most important therapeutic target for the treatment of major depression and anxiety disorders. We report an innovative, versatile, and target-selective quantum dot (QD) labeling approach for SERT in single Xenopus oocytes that can be adopted as a drug-screening platform. Our labeling approach employs a custom-made, QD-tagged indoleamine derivative ligand, IDT318, that is structurally similar to 5-HT and accesses the primary binding site with enhanced human SERT selectivity. Incubating QD-labeled oocytes with paroxetine (Paxil), a high-affinity SERT-specific inhibitor, showed a concentration- and time-dependent decrease in QD fluorescence, demonstrating the Utility of our approach for the identification of SERT modulators. Furthermore, with the development of ligands aimed at other pharmacologically, relevant target, our approach May potentially form the basis for a multitarget drug discovery platform.

• 出版日期2011-11-9