Protein interaction-targeted drug discovery: evaluating critical issues.

Employment of the decision strategies outlined in this general discussion should help to pinpoint mode of activity in drug development and validation. Overall, as a paradigm for drug development, a search for small molecules that can interfere with PPIs would seem to have significant long term potential. At present, the level of structural knowledge in databases is not sufficient to predict in toto the protein binding properties of a modeled drug, but as databases improve, this may become generally feasible. A major point that remains to be determined is how much specificity of protein binding can be incorporated into molecules of generally less than 500 Da. Finally, integration of PPI-targeting strategies with other approaches towards drug design will enhance the number of signaling pathways that can effectively be targeted. These points will be particularly pertinent as technologies permit a systematic identification of encoded protein interactions that govern the proteornic complement of cells.