For those of you interested in fragment screening (and especially for those who are thinking of trying it out), Ben Davis of Vernalis and Dan Erlanson of Carmot Therapeutics have written an excellent guide to avoiding the common experimental problems. (Remarkably, at least to me, Elsevier has made this an open-access article). In fact, I'd recommend the article to everyone doing early-stage compound discovery, whether they're into fragments or not, because many of the issues it raises are universal.
. . .Clearly the approach works, but that is not to say it is easy. This Digest focuses on an area we believe is still insufficiently appreciated: the myriad pitfalls and artifacts that can befall a fragment-screening program. For the sake of brevity, we have chosen to focus on the problems that can hinder or derail an experimental fragment screening campaign; a full discussion of issues around fragment library design, virtual fragment screening, and fragment evolution is best dealt with elsewhere. . .
. . .Today many techniques are used to identify fragments, each with its own strengths. Importantly, however, each of these techniques also has unique limitations. While expert users are generally aware of these and readily pick out the signal from the noise, newcomers are often deceived by spurious signals. This can lead to resources wasted following up on artifacts. In the worst cases—unfortunately all too common—researchers may never realize that they have been chasing false positives, and publish their results. At best, this is an embarrassment, with the researchers sometimes none the wiser. At worst it can cause other research groups to waste their own resources. . .
They go into detail on difficulties with compound identity and stability (on storage and under the assay conditions). You've got your aggregators, your photoactive compounds, your redox cyclers, your hydrolytically unstable ones, etc., all of which can lead to your useless assay results and your wasted time. Then there's a discussion of the limits of each of the popular biophysical screening techniques (and they all have some), emphasizing that if you're going to do fragment screening, that you'd better be prepared to do more than one of these in every campaign. (They are, of course, quite right about this - I've seen the same sorts of situations that they report, where different assays yield different hit sets, and it's up to you to sort out which of those are real).
Highly recommended, as I say. These guys really know what they're talking about, and the drug discovery literature would be greatly improved if everyone were as well-informed.