11 March 2015

The Sequel is Never as Good as the Original

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".


Anonymous said...

Its not really a phenotypic fragment screen. Its a biochemical fragmnet screen that jumps straight to a cellular assay as hit 'confirmation'.

Dr. Teddy Z said...

I think that is a much better way of putting it.

Anonymous said...

But, fragments have proven to be highly utile in liganding these targets.

But flowery speech is proven to be futile in luring us to read these posts.

Gordon Saxty said...

Any idea how this 185 Da compound was discovered? http://en.wikipedia.org/wiki/Pirfenidone

Dr. Teddy Z said...

@anonymous2, Is this my "It was a dark and stormy night"?

@Gordon, no. Fragment screening?