We are living in a target-driven environment in Pharma, for both good and bad. The low-hanging fruit have been plucked and the high-hangers are tough. But, fragments have proven to be highly utile in liganding these targets. One drawback with target-based screening is the problem with cellular activity, while it may be easy to generate good activity against the isolated target, in the end you need activity in the cell/animal. Back in the good ole days, people just skipped the target and went straight into cells: compounds are put on bacterial plates and the microbes die if the compound is anti-microbial. This is the simplest example of phenotypic screening, the phenotype here being "dead cells". [For a discussion of the history of phenotypic screening, go here.] Fragments could be the worst case scenario for phenotypic screening as fragment-target interactions are very weak, and very commonly do not exert a biological effect.
In this paper from Rob Leurs and colleagues, including Iota, the describe a fragment-based phenotypic screen process. This work is a follow on to previous work from this group discussed here, which I quite liked So, they have a target (PDEB1) but immediately follow their screening with the phenotypic part. For the phenotypic screen, they used several different parasitic PDE and MRC5 cell-line as a counter-screen. I won't bore you with any of the experimental details. The compounds are recapitulating known molecules, like benadryl. Now, I really wanted to like this paper, at least from a process approach. It appears to my eyes, that all the compounds are pretty much equipotent and cytotoxic. This is a really disappointing paper in that it doesn't really do anything. They had shown previously that you could get non-cytotoxic compounds with good inhibition of PDEB1. They didn't repeat that here. There is no X-ray, they did before. The compounds are wholly uninteresting and stretch the imagination to be seen as compounds "with a lot of potential to grow into antiparasitic compounds".