Allostery in Drug Discovery

Most drugs on the market are designed to bind directly to primary active, so-called orthosteric, sites. Allosteric modulators offer important advantages over orthosteric ones: they can be more selective because allosteric sites are less conserved, they can change protein levels or localization within the cell, change subtle aspects of protein function and are unique in their ability to provide target activation. Furthermore, allosteric drugs can be used synergistically with orthosteric ligands, an approach that has been successfully used to prevent emergence of resistance in cancer therapy. Up to date in the literature, the discovery of allosteric binding sites and lead compounds targeting those sites has been mostly serendipitous, achieved through high-throughput screening or modification of endogenous allosteric ligands and subsequent follow up experimental work on the mechanism of action, but not rational design. In the framework of the EU ITN ALLODD, focusing on the allostery in drug discovery, we and many other partners from academia and industry are developing new tools to predict, understand and rationally explore allostery as a principle in drug development.