A few months ago we highlighted a forum in Nature comparing fragment-based lead discovery with diversity-oriented synthesis, or DOS. This was quite a vigorous debate and was covered on our sister blog as well as In the Pipeline and second messenger. Personally I’ve never been a this or that kind of guy – more of a this and that – so it is refreshing to see a paper in this week’s issue of PNAS describing a DOS approach to building fragments.
Damian Young and colleagues at Harvard and the Broad Institute, ground zero for DOS, noted that many commercial fragments contain a sizable percentage of sp2 carbons: aromatic rings, for example. Because a larger number of aromatic rings correlates with lower solubility and higher attrition in lead development, the researchers focused on using DOS to generate fragments that would have a higher fraction of sp3 carbons at the expense of sp2 carbons. They used a “build/couple/pair” approach, in which chiral “building blocks” (in this case proline derivatives) were “coupled” to another building block and then functional groups were “paired” to generate bicyclic molecules. The result was about three dozen fragments.
So how do they look? Actually, not so bad. Superficially they all resemble one another, but because they contain up to three stereocenters they cover quite a bit of chemical space while still conforming to the rule of 3. Significantly, they are in fact more three-dimensional than commercially available fragments (from ZINC) having the same molecular formula or the same set of calculated physical properties (molecular weight, cLogP, number of hydrogen-bond donors and acceptors, etc.). The DOS fragments contain a larger fraction of methyl esters and carboxylic acids than I would want to see in a library overall, but this was intentional, and none of them are downright ugly.
Unfortunately the paper provides no screening data, so it is anyone’s guess whether any of the fragments will turn out to be active. Still, the approach is likely to probe new areas of chemical space. Hopefully some of the commercial purveyors of fragments will start making and selling these types of molecules.