Of the nearly half-million proteins in the human body, encoded by twenty-thousand genes in the human genome, only 754 of them have ever been successfully targeted by FDA approved drugs.
Druggable proteins tend to be those with deep clefts or pockets, into which you can insert a drug - much like a key into a padlock. Thus, typical drugs fill the binding site, excluding water. "Undruggable" proteins, however, require drugs that bind to the flat surfaces of the protein, and bind despite the presence of water.
In order to drug the undruggable, you need to be able to understand and predict the forces at work with the high accuracy, beyond the technologies that have been used for the past 40 years.