High-throughput Screening Technology for Selective Inhibitors of Transporters and Its Application in Drug Discovery

The first step in small-molecule drug discovery is the identification of hit compounds via high-throughput screening (HTS) . In transporter drug discovery, most HTS assays are based on the uptake of labeled substrates, but such functional assays cannot be developed for many transporters, such as intracellular organelle transporters. These transporters remain unexplored in drug discovery despite their promise as drug targets. Affinity selection-mass spectrometry (AS-MS) is a label-free binding assay technology that has been developed as an HTS technology for analyzing interactions between targets and compounds. The use of AS-MS technology enables HTS against every type of drug target, in contrast to functional assays. AS-MS technology is usually used for soluble proteins, but we have developed this technology for application to membrane proteins as well. So far, we have used AS-MS for HTS of approximately 400000 compounds. In this review, the principles and application of AS-MS technology are introduced and an HTS campaign for solute carrier type 17A8 (SLC17A8) (vesicular glutamate transporter 3) is presented as an example.