There are a lot of topics that we really should know more about in drug discovery, but which are buried inside projects inside particular organizations. Some of this knowledge is available once you’re inside said organization, but some of it is hard to assemble even then (much less into a review from outside). An example is the impact of structure-based drug design. There’s no doubt that it has had a major influence in some projects, but it’s hard to quantify.
There are, of course, projects that can be largely ruled out, since there isn’t really a structure for the protein target (and thus certainly not one with a ligand bound). But that still leaves you with a lot of projects where effort goes into getting such data: if you have a protein that can crystallize, it’s really negligent if you don’t give it a shot. But I’m not aware of a recent review or list of structure-based successes (where key insights were gained this way), even though I know that they’re out there, and have been involved with some myself. These tend to be a paragraph inside a longer paper, when the project gets published at all, so it’s no easy job to track them down.
With that in mind, I’d like to throw this question open to the readership: what are some recent examples? My guess is that fragment-based drug design is where many of them will turn up, since you really want to know the details of your fragment binding modes. But there must be many times where a particular methyl group’s or hydrogen bond’s role became apparent in an X-ray structure and informed the rest of the SAR development in a crucial way. I’d be interested in hearing if anyone has been able to get this sort of thing done by NMR techniques as well. In a few years, we’ll be asking about the influence of ligand-bound structures via cryo-EM, the way things are going, but for now I’ll bet it’s almost entirely X-ray work.
So what’s the state of the field? Is the value of structure-based methods so apparent that no one notes it so much anymore? Are there programs that got ligand-bound structures but found that these provided no particular insights? Or are there some clear success stories that have been highlighted but not collected into any one place? Examples welcome.