Strategies and methods in the identification of antagonists of protein-protein interactions.

The identification of antagonists of protein-protein interactions is a critical challenge to the pharmaceutical industry. The selection of a protein target, which is amenable to antagonism, is the first of many decisions that determine the success of these efforts. In addition, the definition of strategies and the development and application of methodologies appropriate to that target will be vital to the success of efforts to identify antagonists of a protein-protein interaction. An analysis of current approaches to the identification of lead molecules demonstrates that a search for competitors of a known binder is the basis of traditional screening as well as more modern approaches based on structure activity relationship (SAR) by nuclear magnetic resonance (NMR), molecular fragments, rational design, and tethering. The latter methods employ a structural perspective, throughout the discovery and optimization of a lead, to provide the practitioner with some control over the success of the process.