Fragments of the future

We recently provided a list of suppliers of commercial fragment libraries. A problem with buying compounds from these sources, of course, is that all your competitors can buy the same compounds. And while talented medicinal chemists are adept at turning common fragments into novel clinical candidates, it’s awfully nice to start with fresh fragments (see here for examples of both).

Researchers at UCB Celltech have recently taken this to an interesting extreme: they’ve computationally enumerated all neutral mono- and bicyclic 5 and 6 membered heteroaromatic rings containing carbon, nitrogen, oxygen, sulfur, and hydrogen. The resulting VEHICLe (virtual exploratory heterocylic library) is a set of 24,847 ring systems, of which only 1701 have been reported.

Of course, as the authors note, many of the remaining molecules “are outlandish and would obviously be either very difficult or impossible to make.” To address this, they used a machine learning approach to gauge synthetic tractability. This resulted in over 3000 molecules, some of which look quite reasonable:



Interestingly, the researchers estimate that only 5 to 10 of these heterocycles are being made each year, which leaves hundreds of virgin synthetic targets.

Are these a rich source of new fragments? Or, as the authors also speculate, do many of these lie outside biological activity space?