Understanding cellular processes at molecular levels in health and disease requires the knowledge of protein-protein interactions (PPIs). In line with this, identification of PPIs at genome-wide scale is highly valuable to understand how different cellular pathways are interconnected, and it eventually facilitates designing effective drugs against certain PPIs. Furthermore, investigating PPIs at a small laboratory scale for deciphering certain biochemical pathways has been demanded for years. In this regard, yeast two hybrid system (Y2HS) has proven an extremely useful tool to discover novel PPIs, while Y2HS derivatives and novel yeast-based assays are contributing significantly to identification of protein-drug/inhibitor interaction at both large- and small-scale set-ups. These methods have been evolving over time to provide more accurate, reproducible and quantitative results. Here we briefly describe different yeast-based assays for identification of various protein-protein/drug/inhibitor interactions and their specific applications, advantages, shortcomings, and improvements. The broad range of yeast-based assays facilitates application of the most suitable method(s) for each specific need.
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