Update: I've heard from both the lead author of this paper and one of its reviewers, and I've written a follow-up post on this subject, as well as revising this one where shown below.
I've been saved the trouble of demolishing this J. Med. Chem. paper - the Practical Fragments blog has done it for me. I really hate to say such things, but this appears to be one of the worst papers that journal has published in quite a while.
The authors start out with a small,
poorly documented (update: the compounds are, in fact, in the paper's supplementary information, but see the follow-up post) library of fragment compounds. They screen these against dihydrofolate reductase, and get a few possible hits - mind you, there's not much correlation between the numbers and any potency against the enzyme, but these aren't potent compounds, and fragment-level hits don't always perform in high-concentration enzyme assays. But what happens next? The authors string these things together into huge dimeric molecules, apparently because they think that this is a good idea, but they get no data to support this hypothesis at all.
Well, their potency goes from low millimolar to low micromolar, but as Teddy Z at Practical Fragments points out, this actually means taking a terrible beating in ligand efficiency. All that extra molecular weight should buy you a lot more potency than this. There's some hand-waving docking of these structures - which the authors themselves refer to as "poorly optimized" - and some inconclusive attempts at X-ray crystallography, leading to uninterpretable data.
And that's it. That's the paper.
This on a class of enzymes that's been worked on for decades, yet. (Update: this characterization is completely wrong on my part - see the follow-up post linked to above for more). Again, I hate to be unkind about this, but I cannot imagine what this is doing in J. Med. Chem., or how it made it through the editorial process. When you submit a scientific manuscript for publication, you open yourself to comments from all comers, and those are mine.