The Evolving Role of Structural Biology in Drug Discovery

Modern drug discovery is a highly complex and multi-disciplinary activity that began at the turn of the twentieth century, and structural biology started to have an impact in the seventies. The first drug derived from a structure-based approach, the antihypertensive captopril, an angio-tensin-converting enzyme inhibitor, was approved in 1981, followed by dorzolamide, a carbonic anhydrase inhibitor used for the treatment of glaucoma, in 1995. Structural biology has been fully integrated in the pharmaceutical industry drug discovery pipeline, and many companies use both high-throughput screening and fragment screening to identify starting points for their small-molecule R&D programs. Two important criteria for pursuing a drug target are its druggability and the possibility to design selective drugs that do not bind closely related proteins to avoid potential adverse effects. Cryo-electron microscopy will be a most useful complementary technique to answer biological questions, mostly by addressing large and/or dynamic macromolecular complexes and challenging targets such as membrane proteins.