Here's a paper on a high-throughput screening issue that everyone in the field should be aware of: metal impurities in your compounds. The group (from Roche) describes a recent experience, and I think that many readers will shiver in recognition:
The hits were resynthesized, and close analogues were prepared for early structure−activity relationship (SAR) exploration. All three series lacked conclusive SAR. Most exemplifying are the activities of different batches of the very same compounds that exhibited very different activities from being low micromolar to inactive with IC50 values greater than one millimolar (Table 1). Additionally, the SAR of close analogues was either flat or very steep as indicated by compounds with minimal structural changes losing all activity (data not shown).
For these particular hits, we investigated these findings further. It was discovered that for one series, different routes of synthesis were used for the original preparation of the HTS library compound and its resynthesis. The historic synthesis made use of a zinc/titanium reduction step, whereas the new synthesis leading to inactive compounds did not. The schemes to prepare compounds of the other series also had steps involving zinc. Elemental analysis of the samples to determine the zinc content revealed that the active batches contained different amounts of zinc of up to 20% of total mass, whereas the inactive batches only had traces. . .
I think that many of us have been burned by this in the past, but it's something that should be out there in the literature so that it's easier to make the case to those who haven't heard about it. The Roche group suggests a counterscreen using a zinc chelator (TPEN) that will get rid of zinc-based effects. They pulled out 90 of their hits based on that work, and checking those against past assays showed that they had unusually high hit rates across the years. Some of them had, in fact, been considered hits for current Roche projects, and checking those assays showed that they were sensitive to zinc as well.
I can tell you from personal experience that the stuff can be a real problem. In that case, "impurity" was a relative term - the compound from the files turned out to be a 1:1 zinc complex, not that this little fact was noted anywhere in its (rather ancient) documentation from inside the company.
And I've seen copper do the same sort of thing. I would very much recommend checking out any active compound that looks to have been made by Ullmann chemistry or the like. I mean, I like the Ullmann reaction (and it looks like I may be setting some of them up soon), but there's a lot of copper in those things, and some assays are very sensitive to it. In extreme cases, I've seen compounds come in from custom synthesis houses that were colored green from the stuff, and that's just not going to work out. There are regrettably few lead-like compounds that come by a green tint honestly: you're looking at copper, maybe chromium, or perhaps even nickel, none of which will help you generate reliable assay numbers. Don't even let the green stuff into your collection, if you can - clean it up first, and complain to the people who sent it to you. (Note, by contrast, that zinc complexes tend to show no added colors).
Jonathan Beall speculated to me in an e-mail that maybe this is one way that frequent-hitter compounds can get on such lists, by coordinating metals. It's certainly possible. Ignore metals at your peril!