Universal strategies in research and drug discovery based on protein-fragment complementation assays

Changes in the interactions among proteins that participate in a biochemical pathway can reflect the immediate regulatory responses to intrinsic or extrinsic perturbations of the pathway. Thus, methods that allow for the direct detection of the dynamics of protein-protein interactions can be used to probe the effects of any perturbation on any pathway of interest. Here we describe experimental strategies - based on protein-fragment complementation assays (PCAs) - that can achieve this. PCA-based strategies can be used with or instead of traditional target-based drug discovery strategies to identify novel pathway-component proteins of therapeutic interest, to increase the quantity and quality of information about the actions of potential drugs, and to gain insight into the intricate networks that make up the molecular machinery of living cells.