Dan and I are at the CHI Discovery on Target meeting in Boston. We taught our award-winning course on FBDD yesterday, but with an emphasis on PPI. And just in time, Andrew Turnbull, Susan Boyd, and Bjorn Walse published a paper on PPIs and FBDD (it's open access[Ed:Link fixed]). The paper is a nice review of PPIs in general (which have already been covered here): structural characteristics, the "hot spot", and computational approaches. What I thought interesting was their discussion of the physico-chemical properties of PPI fragments. This is an area were this is a lot of common knowledge, but nothing rigorously studied. So, into the breach.
They discuss vendor supplied PPI libraries: Asinex, Otava (which does not seem to be a fragment library with a mean MW of~500), and Life Chemicals. PPI compounds are thought to need to be more 3D and obey the rule of 4: PPI compounds will tend to be larger and more lipophilic. Does ontogeny recapitulate philogeny? To explore this, they looked at 100 fragments orthosterically active against PPI targets (unpublished data) and compared to 100 fragments active against non-PPI targets.
It appears that PPI fragments are a little larger and more lipophilic than "standard" fragments, but NOT any more 3D. It should also be noted that the PPI fragments had double the acid and base containing fragments than "standard" fragments. The authors agree that their dataset is small, and other groups are looking at larger datasets. But, the conclusion they draw is that PPI fragments should be larger, more lipophilic, and contain at least one polar moiety.