04 February 2011

Fragments in Nature

The most recent issue of Nature has a brief but trenchant summary of fragment-based screening (FBS) by Abbott’s Phil Hajduk, of SAR by NMR fame. This is the first half of a drug discovery forum comparing FBS with diversity-oriented synthesis, or DOS, covered by Warren Galloway and David Spring of the University of Cambridge.

Hajduk summarizes the advantages of FBS:
Fragment libraries are more diverse, synthetic resources are used more efficiently and the leads identified from FBS are more likely to yield drug candidates that have optimal physico-chemical properties.
He also points out that fragment-based approaches have led to a number of drugs in the clinic.

In the spirit of “vigorous debate,” Hajduk also takes aim at DOS. In comparison with fragment-based approaches, which start with small libraries of small fragments, DOS generally makes use of larger libraries of structurally diverse molecules which are usually drug-sized and are often inspired by natural products. However, Hajduk alleges that:
Most compounds in DOS libraries would be excluded from many corporate screening collections because of their poor physico-chemical properties.
I don’t know about “most”, but I will say that many DOS compounds look suspiciously like PAINS. Still, DOS does have at least one strength: FBS is generally limited to well-characterized systems with purified proteins, whereas DOS libraries can be used in complex phenotypic assays where the target may not be known. Whether these will ultimately yield new drugs remains to be seen.

What do you think?


Anonymous said...

Reminds of the comment on DOS libraries here:

"So no, I wouldn't have bought this set for screening, either; I'd have cherry-picked about 15 or 20% of it."

Dan Erlanson said...

Good catch - In the Pipeline has written something about this forum too:


Pete said...

Now also reviewed in the other fragment blog and set up as LinkedIn discussion.