Seminar

Structural Biology in Drug Discovery

Giovanna Scapin, PhD

The drug discovery process is lengthy and very expensive. A recent estimate by the Tufts Center for the Study of Drug Development puts the cost to more than $2.4 billion while the time from discovery to approval can be as long as 15 years. Failure rate is also high, and on average only 10% of the drugs that make it into Phase 1 have some probability of being approved. Structural knowledge can inform and accelerate many of the drug discovery and development steps, and in most cases this knowledge is derived not by a single technique, but a combination of biochemical, and biophysical approaches. Knowledge of the three-dimensional architecture of the target molecule is best useful when the information derived from it is valid in its biological contest, and it can provide new ideas and hypothesis that can be independently tested and verified. This is most evident when structural information is used to characterize and validate targets, for example by guiding the design of potent and specific small molecule tools, evaluating the effects of mutations on diseases, or informing genetic and mutagenesis studies. The greatest impact of structural biology during drug discovery can be probably seen in the lead identification and optimization steps, and some of these applications will be discussed during the presentation. Applications of crystallography during late stages of drug discovery are rarer, but examples can still be found. For example, crystalline suspensions have been demonstrated to be useful alternatives for drug delivery for small molecules as well as biologics. The search for better crystalline suspension for antibody delivery at MSD lead to two unforeseen results: a long term collaboration with CASIS and NASA for micro-gravity experiments, and the elucidation of the three-dimensional structure of pembrolizumab, an IgG4 therapeutic antibody. X-ray crystallography, NMR, computational chemistry and biochemical techniques were essential in the determination of this structure, and the understanding of its unusual features, which may suggest new questions about the activity and functions of IgG4.