Nature has side-by-side editorial pieces about fragment-based drug discovery versus diversity-oriented synthesis (DOS). I've written about both topics here before (DOS here and here, fragments here and here), and it should be fairly clear that I favor the former. But both ideas deserve a hearing.
Background, for those who aren't having to think about this stuff: the fragment-based approach is to screen a reasonable set (hundreds to low thousands) of small (MW 150 to 300) molecules. You won't find any nanomolar hits that way, but you will find things that (for that molecular weight) are binding extremely efficiently. If you can get a structure (X-ray, most of the time), you can then use that piece as a starting point and build out, trying to keep the binding efficiency high as you go. Diversity-oriented synthesis, on the other hand, tries to make larger molecules that are in structural spaces not found in nature (or in other screening collections, either). It's a deliberate attempt to make wild-blue-yonder compounds in untried areas, and is often used to screen against similarly untried targets that haven't shown much in conventional screening.
The two articles make their cases, but spend some time talking past each other. Abbott's Phil Hajduk takes the following shots at DOS: that it's tended to produce compounds whose molecular weights are too high (and whose other properties are also undesirable), and that it needs (in order to cover any meaningful amount of chemical space at those molecular weights) to produce millions of compounds, all of which must then be screened. Meanwhile, Warren Galloway and David Spring of Cambridge make the following charges about fragment work: that it only works when you have a specific molecular target in mind (and that only then when you have high-quality structural information), that it tends to perform poorly against the less tractable targets (such as protein-protein interactions), and that fragments (and the molecules derived from them) tend not to be three-dimensional enough.
Here's my take: I like phenotypic screening, where you run compound collections across cells/tissues/small animal models and see what works. And fragment are indeed next to useless for that purpose. But I agree with Hajduk that most of the DOS compound libraries I've seen are far too large and ugly to furnish anything more than a new probe compound from such screens. There are many academic labs for whom that's a perfectly good end point, and they publish a paper saying, in short, We Found the First Compound That Makes X Cells Do Y. Which is interesting, and can even be important, but there's often no path whatsoever from that compound to an actual drug. I'd prefer that DOS collections not get quite so carried away, and explore new structural motifs more in the range of druglike space. But that's not easy - new structures are a lot easier to come by if you're willing to make compounds with molecular weights of 500 to 1000, since (a) not so many people have made such beasts before, and (b) there are a lot more possible structures up there.
Now, if I have a defined target, and can get structures, I'd much prefer to do things the fragment way. But this is where the two editorial talk past each other - they both beat the drum for what they do well, but they do different things well. It's the parts where they overlap that I find most interesting. One of those is, as just mentioned, the problem that DOS compounds tend to be too large and undevelopable (with one solution being to go back and make them more tractable to start with). The other overlap is whether fragment collections can hit well against tough targets like protein-protein interactions. I don't know the answer to that one myself - I'd be glad to hear of examples both pro and con.
So we'll call this a struggle still in progress. With any luck, both techniques will keep each other's partisans on their toes and force them to keep improving.