The advent of real X-ray structures for receptors means that there are many experimental approaches that can now be tried that earlier would have been (most likely) foolhardy. My first research in the industry was on dopamine receptors, which I followed up by a stint on muscarinics, and we really did try to be rational drug designers. But that meant homology models and single-point mutations, and neither of those was always as helpful as you'd like. OK, fine: neither of them were very helpful at all, when you got right down to it. We kept trying to understand how our compounds were binding, but outside of the obvious GPCR features - gotta have a basic amine down there - we didn't get very far.
That's not to say that we didn't make potent, selective compounds. We certainly did, although you'll note that I'm not using the word "drug". For many of them, even the phrase "plausible clinical candidate" is difficult to get out with a straight face, potent and selective though they may have been. We made all these compounds, though, the old-fashioned way: straight SAR, add this on and take that away, fill out the table. Structural biology insights didn't really drive things much.
So when the transmembrane receptor X-ray structures began to show up, my first thought was whether or not they would have helped in that earlier effort, or whether they still had enough rough edges that they might have just helped to mislead us into thinking that we had things more figured out. There's a report, though, in the latest J. Med. Chem. that puts such structures to a pretty good test: can you use them to do fragment-based drug discovery?
Apparently so, at least up to the point described. This is the most complete example yet reproted of FBDD on a G-protein coupled receptor (beta-1 adrenergic). Given the prominence of receptors as drug targets, the late advent of fragment work in this field should tell you something about how important it is to have good structural information for a fragment campaign. I'm not sure if I've ever heard of one being successful without it - people say that it can be done, but I certainly wouldn't want to be the person doing it. That's not to say that X-ray structures are some sort of magic wand (this review should disabuse a person of that notion) - just that they're "necessary, but not sufficient" for getting a fragment program moving at reasonable speed. Otherwise, the amount of fumbling around at the edge of assay detection limits would be hard to take.
The beta-adrenergic receptor is the one with the most X-ray data available, with several different varieties of agonists and antagonists solved. So if any GPCR is going to get the fragment treatment, this would be the one. (There's also been a recent report of a fragment found for an adenosine receptor, which was largely arrived at through virtual screening). In this case, the initial screening was done via SPR (itself a very non-trivial technique for this sort of thing), followed by high-concentration radioligand assays, and eventual X-ray structure. They found a series of arylpiperazines, which are thoroughly believable as GPCR hits, although they don't have much of a history at the adrenergic receptor itself. The compounds are probably antagonists, mainly because they aren't making enough interactions to flip the switch to agonist, or not yet.
This paper only takes things up to this point, which is still a lot farther than anyone would have imagined a few years ago. My guess is that FBDD is still not ready for the spotlight in this field, though. This paper is from Miles Congreve and the folks at Heptares, world experts in GPCR crystallography, and presumably represents something pretty close to the state of the art. It's a proof-of-concept piece, but until the structures of more difficult receptors are available with more regularity, I don't think we'll see too much fragment work in the area. I'd be happy to be wrong about that.