High-throughput screening assays to discover small-molecule inhibitors of protein interactions.

The availability of large collections of small-molecule inhibitors of protein interactions would bear a tremendous impact both on academic and therapeutic research. The past recent years have seen a marked acceleration in the discovery of protein interaction inhibitors, through structure-based drug design but mostly through screening efforts. This article attempts to review the impressive number and variety of in vitro and cellular screening assays that have been developed and, for most of them, used successfully to identify small-molecule inhibitors of protein interactions. Various strategies aimed at improving hit rates are also reviewed, and future challenges to improve discovery success rates are discussed. The growing list of protein interaction inhibitors and the large arsenal of screening methods, now available to most laboratories or screening facilities, will probably convince an increasing number of academic and industrial scientists that protein interactions are more druggable than once feared, and that their respective research interests would greatly benefit from the discovery of protein interaction inhibitors.