Sociable vs unsociable fragments – and poll!

The last two posts described new fragment libraries, one of which is available for screening. But what happens once you get a hit? More than five years ago we highlighted the importance of synthetic tractability for fragments. In a recent RSC Med. Chem. paper, Jeffrey St. Denis and colleagues at Astex assess how easily (or not) researchers can work with the fragments they find.

 

The researchers coin the phrase “fragment sociability”:

 

An unsociable fragment is one that has limited (if any) synthetic methodology to enable growth vector elaboration and few commercially available close analogues. In contrast, a sociable fragment is one supported with robust synthetic methodology that enables every growth vector to be elaborated and a significant number of commercially available close analogues.

 

To illustrate, they summarize three unrelated fragment-to-lead programs from Astex and, for each case, compare an unsociable fragment with a sociable one. For the unsociable fragments, fewer than 10 analogs were commercially available, and if synthetic routes existed, they were lengthy. In contrast, the sociable fragments had from >100 to >1000 commercially available analogs and well-precedented syntheses. Three of the fragments (mexiletine, tetramisole, and efaroxan) are actually drugs targeting other proteins, but surprisingly only mexiletine is sociable. Astex advanced all three sociable fragments to nanomolar inhibitors and abandoned the unsociable fragments.

 

How can you tell if a fragment is sociable or not? The researchers use the Fragment Network (previously described here) as a computational tool to assess commercial availability of analogs. For synthetic tractability, a medicinal chemist should inspect apparently unsociable fragments, as a purely computational approach might miss “double scaffolds,” which consists of two sociable fragments linked together. While the combination may superficially appear unsociable, simple chemistry could be used to connect the two smaller fragments. Similarly, functional group transformations (such as oxidation) might make a sociable fragment appear unsociable, or vice versa.

 

The researchers analyzed the 1651 members of the Astex core screening library and found only 30 possibly unsociable members. More careful examination revealed that only 12 of these are truly unsociable, and even for these, minor changes could make them sociable.  

 

I confess that I’m both surprised and impressed at the low number of unsociable fragments, though as the researchers point out the Astex library has been continuously refined for the past couple decades. Also, if “more esoteric fragments were socialized then they would… provide an opportunity to identify novel starting points in drug discovery.”

 

I’m a huge fan of developing new fragment chemistries. But from a practical standpoint, how much of a need is there? After all, in these three fragment-to-lead examples the researchers were able to obtain potent molecules. FBLD often generates an abundance of riches: 76 and 105 crystallographic hits in two of the programs described.

 

In the spirit of inquiry, Practical Fragments launches a new poll (right side of page) asking how often you’ve encountered synthetic challenges optimizing a fragment, and whether this has impeded a fragment to lead program. Please vote and leave comments!