Yeast two-hybrid methods and their applications in drug discovery

The yeast two-hybrid (Y2H) method was first described over 20 years ago. It soon appeared as a major methodological breakthrough in the discovery and analysis of protein interactions, which play a pivotal role in all biological phenomena. Since its inception the Y2H method has constantly evolved and has inspired various assays that have found multiple applications of interest for drug discovery. Y2H methods are used to identify and validate therapeutic targets, discover protein interaction modulators, identify drug targets, and select combinatorial recognition molecules, which themselves find a wide range of applications. We review here the different transcriptional Y2H methods that are directly useful to drug discovery. Most should be increasingly used in the future as they continue to evolve to harness other methodological and conceptual advances.