Structure-Based Drug Design – A Historical Perspective and the Future

Abstract

Paul Ehrlich in his 1908 Nobel Prize address credits Emil Fischer with the idea that an antitoxin and a toxin could be envisioned to fit as atomic locks and keys. The idea one might someday visualize a receptor lock and design a specific receptor key has captivated those in drug discovery since. Max Perutz paved the way for structure based drug design when he found the solution to phasing x-ray diffraction intensities producing the first three dimensional structure of a protein, hemoglobin. This chapter covers the history of the first groups to employ single crystal x-ray diffraction of large biological molecules with the purpose of discovering a drug. The field has come to be known as Structure-Based Drug Design. Naturally, hemoglobin being involved with a genetic disease Sickle Cell Anemia as well as being a potential target to treat hypoxic diseases, was the first atomic lock to be chosen. The first industrial firm to specialize in using x-ray crystallography was Agouron who initially focused on folate proteins with the idea of discovering anti-tumor agents. Allied field advances in molecular modeling with the real time depiction of three dimensional images, computational chemistry which provided new Newtonian Force Fields to produce low energy structures and methods for docking small and large molecules to active sites, NMR for small proteins imaged in solution and electron diffraction methods that enable imaging of large membrane receptors that do not crystallize have provided those in Structure-Based Drug Design with unparalleled opportunities for not only inventing new medicines but in understanding what really occurs when an atomic key interacts with an atomic lock. Two approaches to Structure-Based Drug Design are covered: de novo design and iterative design. Take home lessons are presented from the first 10 years of Structure-Based Drug Design. A table of protein and receptor targets readily shows the dramatic expansion that occurred once the idea of Structure-Based Drug Design was adopted by all sizes of pharmaceutical houses and in academia. The chapter ends with a look to the future in five different areas that are branching out from the original Structure-Based Drug Design seed that took root.