The researchers started by computationally deconstructing 183,769 natural products into 751,577 component fragments. After various filters (size, lipophilicity, reactivity, etc.) they arrived at 110,485 fragments sorted by similarity into 2000 clusters. The resulting fragments differ in their overall calculated properties from commercial fragments. This is all highly reminiscent of the Emerald (nee deCODE) “fragments of life”, though surprisingly that work is not referenced.
One challenge of designing new fragments is that you may not be able to buy them. In this case, nearly half of the clusters did have a compound that could be purchased – though perhaps this somewhat defeats the purpose of trying to explore novel chemical space. At any rate, 193 fragments were either bought or synthesized. These were tested in functional assays against p38a MAP kinase and several protein phosphatases. A number of hits were identified, and in the case of p38a, nine kinase-fragment co-crystal structures were solved. Some of these were similar to previously reported fragments, but others were more unusual. Together with the crystal structures, these fragments provide new ideas for a well-studied target.
Looking at the structures of some of the phosphatase inhibitors, however, I started to worry. One strong point of the paper is that it is very complete: the chemical structures of all 193 tested fragments are provided in the supplementary information. Unfortunately, the list contains some truly dreadful members; 17 of the worst are shown here, with the nasty bits shown in red. All of these are PAINS that will nonspecifically interfere with many different assays.
Compounds 15, 44, 49, 159, 166, 173, 174, and 175 are catechols; compounds 89 and 151 (yes, they are the same molecule – guess they really liked this one), 165, 166, 167, and 168 are quinones; compounds 55, 89/151, and 166 are hydroquinones; compound 20 is a Michael acceptor; compound 76 is an epoxide; and compound 184 is a redox cycler. In other words, these fragments are a depressing example of life imitating art (or at least satire).
To be blunt: none of these molecules should appear in a screening library today.
I don’t want to pick on these researchers; it is after all laudable that they fully disclosed the structures of their molecules.
However, I am concerned that other people may build libraries containing some of these fragments, or worse, that opportunistic vendors will start selling “natural-product derived fragments.” Indeed, most of these molecules are commercially available. It is disappointing that so many nuisance compounds would find their way into research published in a Nature family journal, and I think it is important to call it out. Only by publicizing the problems that can arise will people be made aware of the dangers.